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Do Abaloparatide and Methyldopa interact?

•Drug A: Abaloparatide •Drug B: Methyldopa •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Methyldopa is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Methyldopa is indicated for the management of hypertension as monotherapy or in combination with hydrochlorothiazide. Methyldopa injection is used to manage hypertensive crises. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Antihypertensive effects of methyldopa are mostly mediated by its pharmacologically active metabolite, alpha-methylnorepinephrine, which works as an agonist at central inhibitory alpha-adrenergic receptors. Stimulation of alpha-adrenergic receptors leads to decreased peripheral sympathetic tone and reduced arterial pressure. Methyldopa causes a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine. Overall, methyldopa lowers both standing blood pressure and especially supine blood pressure, with infrequent symptomatic postural hypotension. Methyldopa also reduces plasma renin activity but has negligible effects on glomerular filtration rate, renal blood flow, or filtration fraction. It also has no direct effect on cardiac function but in some patients, a slowed heart rate may occur. Following oral administration, blood-pressure-lowering effects are observed within 12 to 24 hours in most patients, and a maximum reduction in blood pressure occurs in 4 to 6 hours. Blood pressure returns to pre-treatment levels within 24 to 48 hours following drug discontinuation. Following intravenous administration, the blood-pressure-lowering effects of methyldopa last for about 10 to 16 hours. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The exact mechanism of methyldopa is not fully elucidated; however, the main mechanisms of methyldopa involve its actions on alpha-adrenergic receptor and the aromatic L-amino acid decarboxylase enzyme, to a lesser extent. The sympathetic outflow is regulated by alpha (α)-2 adrenergic receptors and imidazoline receptors expressed on adrenergic neurons within the rostral ventrolateral medulla. Methyldopa is metabolized to α‐methylnorepinephrine via dopamine beta-hydroxylase activity and, consequently, alpha-methylepinephrine via phenylethanolamine-N-methyltransferase activity. Mediating the therapeutic effects of methyldopa, α‐methylnorepinephrine and α-methylepinephrine active metabolites are agonists at presynaptic alpha-2 adrenergic receptors in the brainstem. Stimulating alpha-2 adrenergic receptors results in the inhibition of adrenergic neuronal outflow and attenuation of norepinephrine release in the brainstem. Consequently, the output of vasoconstrictor adrenergic signals to the peripheral sympathetic nervous system is reduced, leading to a reduction in blood pressure. The L-isomer of alpha-methyldopa also reduces blood pressure by inhibiting aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase, which is an enzyme responsible for the syntheses of dopamine and serotonin. Inhibiting this enzyme leads to depletion of biogenic amines such as norepinephrine. However, inhibition of aromatic L-amino acid decarboxylase plays a minimal role in the blood-pressure‐lowering effect of methyldopa. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Methyldopa is incompletely absorbed from the gastrointestinal tract following oral administration. In healthy individuals, the inactive D-isomer is less readily absorbed than the active L-isomer. The mean bioavailability of methyldopa is 25%, ranging from eight to 62%. Following oral administration, about 50% of the dose is absorbed and T max is about three to six hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution ranges between 0.19 and 0.32L/kg and the total volume of distribution ranges from 0.41 to 0.72L/kg. Since methyldopa is lipid-soluble, it crosses the placental barrier, appears in cord blood, and appears in breast milk. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Methyldopa is less than 15% bound to plasma proteins and its primary metabolite, O-sulfate metabolite, is about 50% protein bound. Following intravenous administration, approximately 17% of the dose in normal subjects were circulating in the plasma as free methyldopa. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Two isomers of methyldopa undergo different metabolic pathways. L-α-methyldopa is biotransformed to its pharmacologically active metabolite, alpha-methylnorepinephrine. Methyldopa is extensively metabolized in the liver to form the main circulating metabolite in the plasma, alpha (α)-methyldopa mono-O-sulfate. Its other metabolites also include 3-O-methyl-α-methyldopa; 3,4-dihydroxyphenylacetone; α-methyldopamine; and 3-O-methyl-α-methyldopamine. These metabolites are further conjugated in the liver to form sulfate conjugates. After intravenous administration, the most prominent metabolites are alpha-methyldopamine and the glucuronide of dihydroxyphenylacetone, along with other uncharacterized metabolites. D-α-methyldopa, which is the inactive isomer of methyldopa, is also metabolized to 3-O-methyl-α-methyldopa and 3,4-dihydroxyphenylacetone to a minimal extent; however, there are no amines (α-methyldopamine and 3-O-methyl-α-methyldopamine) formed. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 70% of absorbed methyldopa is excreted in the urine as unchanged parent drug (24%) and α-methyldopa mono-O-sulfate (64%), with variability.3-O-methyl-α-methyldopa accounted for about 4% of urinary excretion products. Other metabolites like 3,4-dihydroxyphenylacetone, α-methyldopamine, and 3-O-methyl-α-methyldopamine are also excreted in urine. Unabsorbed drug is excreted in feces as the unchanged parent compound. After oral doses, excretion is essentially complete in 36 hours. Due to attenuated excretion in patients with renal failure, accumulation of the drug and its metabolites may occur, possibly leading to more profound and prolonged hypotensive effects in these patients. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The plasma half-life of methyldopa is 105 minutes. Following intravenous injection, the plasma half-life of methyldopa ranges from 90 to 127 minutes. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The renal clearance is about 130 mL/min in normal subjects and is decreased in patients with renal insufficiency. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The lowest published toxic dose via oral route is 44 gm/kg/3Y (intermittent) in a female. Oral LD 50 is 5000 mg/kg in rats and 5300 mg/kg in mice. Intraperitoneal LD 50 is 300 mg/kg in rats and 150 mg/kg in mice. Acute overdosage is characterized by acute hypotension and other presentations attributed to the brain and gastrointestinal dysfunction, such as excessive sedation, weakness, bradycardia, dizziness, light-headedness, constipation, distention, flatus, diarrhea, nausea, and vomiting. Symptomatic and supportive measures should be initiated in the event of methyldopa overdose. Overdosage following recent oral ingestion can be managed by gastric lavage or emesis, as well as infusions to limit further drug absorption. Cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity should be closely monitored. The use of sympathomimetic drugs such as levarterenol, epinephrine, and metaraminol bitartrate, or dialysis may be considered. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-(-)-alpha-Methyldopa 3-Hydroxy-alpha-methyl-L-tyrosine Alpha medopa (common) alpha-Methyl dopa (common) alpha-methyl-L-dopa Alphamethyldopa (common) AMD Anhydrous methyldopa L-alpha-Methyldopa (common) L-Methyl Dopa (common) Methyl dopa (common) Methyldopa (common) Methyldopa anhydrous metildopa (common) α-Methyl dopa α-methyl-L-dopa

Do Abaloparatide and Methylene blue interact?

•Drug A: Abaloparatide •Drug B: Methylene blue •Severity: MODERATE •Description: Methylene blue may increase the orthostatic hypotensive activities of Abaloparatide. •Extended Description: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. •References: 1. Cockhill LA, Remick RA: Blood pressure effects of monoamine oxidase inhibitors--the highs and lows. Can J Psychiatry. 1987 Dec;32(9):803-8. [https://go.drugbank.com/articles/A36302] 2. Remick RA, Froese C: Monoamine oxidase inhibitors: clinical review. Can Fam Physician. 1990 Jun;36:1151-5. [https://go.drugbank.com/articles/A36361] 3. Delini-Stula A, Baier D, Kohnen R, Laux G, Philipp M, Scholz HJ: Undesirable blood pressure changes under naturalistic treatment with moclobemide, a reversible MAO-A inhibitor--results of the drug utilization observation studies. Pharmacopsychiatry. 1999 Mar;32(2):61-7. doi: 10.1055/s-2007-979193. [https://go.drugbank.com/articles/A36609] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia. Other clinical applications of methylene blue include improvement of hypotension associated with various clinical states, an antiseptic in urinary tract infections, treatment of hypoxia and hyperdynamic circulation in cirrhosis of liver and severe hepatopulmonary syndrome, and treatment of ifofosamide induced neurotoxicity. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Main mechanism of action involves inhibition of nitric oxide synthase and guanylate cyclase. In Alzheimers Disease: a mechanistic study found that methylene blue oxidizes cysteine sulfhydryl groups on tau to keep tau monomeric. One preclinical treatment study in tauopathy mice reported anti-inflammatory or neuroprotective effects mediated by the Nrf2/antioxidant response element (ARE); another reported insoluble tau reduction and a learning and memory benefit when given early. In Methemoglobinemia: Methylene Blue acts by reacting within RBC to form leukomethylene blue, which is a reducing agent of oxidized hemoglobin converting the ferric ion (fe+++) back to its oxygen-carrying ferrous state(fe++). As antimalarial agent: Methylene Blue, a specific inhibitor of P.falciparum glutathione reductase has the potential to reverse CQ resistance and it prevents the polymerization of haem into haemozoin similar to 4-amino-quinoline antimalarials. For ifosfamide induced neurotoxicity: Methylene blue functions as an alternate electron acceptor. It acts to reverse the NADH inhibition caused by gluconeogenesis in the liver while blocking the transformation of chloroethylamine into chloroacetaldehyde. In addition, it inhibits various amine oxidase activities, which also prevents the formation of chloroacetaldehyde. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 10 mg/kg (in rats). •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Methylene blue was reported to bind strongly to rabbit plasma (71–77% of bound drug). •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Following distribution into tissues, rapidly reduced to leukomethylene blue (leucomethylthioninium chloride). Metabolism to leucomethylene blue may be less efficient in neonates than in older individuals. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Excreted in urine and bile. About 75% of an oral dose excreted in urine, primarily as stabilized colorless leukomethylene blue. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 5–6.5 hours (after IV dose). •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 3.0 ± 0.7 L/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD50 = 1180 mg/kg ( Rat ). •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Hyophen, Phosphasal, Provayblue, Proveblue, Urelle, Uribel, Urimar Reformulated Oct 2013, Urin DS, Urogesic Blue Reformulated Apr 2012, Ustell •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azul de metileno (common) Basic Blue 9 (common) C.I. basic blue 9 (common) Chlorure de méthylthioninium (common) Cloruro de metiltioninio (common) Lowacryl blue 9 Methylene blue (common) Methylene blue anhydrous Methylenium ceruleum (common) Methylthioninii chloridum (common) Methylthioninium chloride (common) Solvent blue 8 Swiss blue

Do Abaloparatide and Metolazone interact?

•Drug A: Abaloparatide •Drug B: Metolazone •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Metolazone is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Metolazone is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. A proximal action of metolazone has been shown in humans by increased excretion of phosphate and magnesium ions and by a markedly increased fractional excretion of sodium in patients with severely compromised glomerular filtration. This action has been demonstrated in animals by micropuncture studies. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The actions of metolazone result from interference with the renal tubular mechanism of electrolyte reabsorption. Metolazone acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule. Sodium and chloride ions are excreted in approximately equivalent amounts. The increased delivery of sodium to the distal tubular exchange site results in increased potassium excretion. Metolazone does not inhibit carbonic anhydrase. The antihypertensive mechanism of action of metolazone is not fully understood but is presumed to be related to its saluretic and diuretic properties. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Peak blood levels are obtained within 2 to 4 hours of oral administration. The rate and extent of absorption are formulation dependent. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 50-70% bound to erythrocytes, up to 33% bound to plasma proteins, 2-5% of the drug in circulation is unbound •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Not substantially metabolized. 70-95% is excreted unchanged in urine via glomerular filtration and active tubular secretion. Undergoes enterohepatic recycling. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Most of the drug is excreted in the unconverted form in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Approximately 14 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include difficulty breathing, dizziness, dizziness on standing up, drowsiness, fainting, irritation of the stomach and intestines, and lethargy leading to coma. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Mykrox, Zaroxolyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-Methyl-3-o-tolyl-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone 7-Chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulfonamide 7-Chloro-1,2,3,4-tetrahydro-2-methyl-4-oxo-3-o-tolyl-6-quinazolinesulfonamide Metolazon (common) Metolazona (common) Métolazone (common) Metolazone (common) Metolazonum (common)

Do Abaloparatide and Metoprolol interact?

•Drug A: Abaloparatide •Drug B: Metoprolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Metoprolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Metoprolol is indicated for the treatment of angina, heart failure, myocardial infarction, atrial fibrillation, atrial flutter and hypertension. Some off-label uses of metoprolol include supraventricular tachycardia and thyroid storm. All the indications of metoprolol are part of cardiovascular diseases. These conditions correspond to a number of diseases that involve the function of the heart and blood vessels. The underlying causes of these conditions are variable and can be due to genetic disposition, lifestyle decisions such as smoking, obesity, diet, and lack of exercise, and comorbidity with other conditions such as diabetes. The cardiovascular diseases are the leading cause of death on a global scale. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Administration of metoprolol in normal subjects is widely reported to produce a dose-dependent reduction on heart rate and cardiac output. This effect is generated due to a decreased cardiac excitability, cardiac output, and myocardial oxygen demand. In the case of arrhythmias, metoprolol produces its effect by reducing the slope of the pacemaker potential as well as suppressing the rate of atrioventricular conduction. The Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) trial showed a significant improvement in sudden cardiac death and myocardial infarction when patients were given with metoprolol as compared with diuretics. As well, in clinical trials performed in 1990, metoprolol reduces mortality and re-infarction in 17% of the individuals when administered chronically after an episode of myocardial infarction. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Metoprolol is a beta-1-adrenergic receptor inhibitor specific to cardiac cells with negligible effect on beta-2 receptors. This inhibition decreases cardiac output by producing negative chronotropic and inotropic effects without presenting activity towards membrane stabilization nor intrinsic sympathomimetics. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): When metoprolol is administered orally, it is almost completely absorbed in the gastrointestinal tract. The maximum serum concentration is achieved 20 min after intravenous administration and 1-2 hours after oral administration. The bioavailability of metoprolol is of 100% when administered intravenously and when administered orally it presents about 50% for the tartrate derivative and 40% for the succinate derivative. The absorption of metoprolol in the form of the tartrate derivative is increased by the concomitant administration of food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The reported volume of distribution of metoprolol is 4.2 L/kg. Due to the characteristics of metoprolol, this molecule is able to cross the blood-brain barrier and even 78% of the administered drug can be found in cerebrospinal fluid. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Metoprolol is not highly bound to plasma proteins and only about 11% of the administered dose is found bound. It is mainly bound to serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Metoprolol goes through significant first-pass hepatic metabolism which covers around 50% of the administered dose. The metabolism of metoprolol is mainly driven by the activity of CYP2D6 and to a lesser extent due to the activity of CYP3A4. The metabolism of metoprolol is mainly represented by reactions of hydroxylation and O-demethylation. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Metoprolol is mainly excreted via the kidneys. From the eliminated dose, less than 5% is recovered unchanged. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The immediate release formulations of metoprolol present a half-life of about 3-7 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The reported clearance rate on patients with normal kidney function is 0.8 L/min. In cirrhotic patients, the clearance rate changes to 0.61 L/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral administration of metoprolol to rats presents an LD50 in the range of 3090 to 4670 mg/kg. Cases of overdose have reported bradycardia, hypotension, bronchospasm, and cardiac failure. In the case of an overdose, gastric lavage is recommended followed by specific treatment according to symptoms. Metoprolol is not reported to be carcinogenic nor mutagenic nor to impair fertility. The only event registered is the increase of macrophages in pulmonary alveoli and slight biliary hyperplasia. When metoprolol was given for long periods of time on the highest dose, there was evidence of small benign lung tumors. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Kapspargo, Lopressor, Lopressor Hct, Toprol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (RS)-Metoprolol (common) 1-(isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol DL-metoprolol (common) Metoprolol (common)

Do Abaloparatide and Metyrosine interact?

•Drug A: Abaloparatide •Drug B: Metyrosine •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Metyrosine. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •References: 1. Lee CH, Strosberg AM, Carver LA: Antihypertensive drugs: their postural hypotensive effect and their blood pressure lowering activity in conscious normotensive rats. Arch Int Pharmacodyn Ther. 1983 Jan;261(1):90-101. [https://go.drugbank.com/articles/A177104] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For use in the treatment of patients with pheochromocytoma, for preoperative preparation of patients for surgery, management of patients when surgery is contraindicated, and chronic treatment of patients with malignant pheochromocytoma. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): In patients with pheochromocytoma, who produce excessive amounts of norepinephrine and epinephrine, administration of one to four grams of metyrosine per day has reduced catecholamine biosynthesis from about 35 to 80 percent as measured by the total excretion of catecholamines and their metabolites (metanephrine and vanillylmandelic acid). The maximum biochemical effect usually occurs within two to three days, and the urinary concentration of catecholamines and their metabolites usually returns to pretreatment levels within three to four days after metyrosine is discontinued. Most patients with pheochromocytoma treated with metyrosine experience decreased frequency and severity of hypertensive attacks with their associated headache, nausea, sweating, and tachycardia. In patients who respond, blood pressure decreases progressively during the first two days of therapy with metyrosine; after withdrawal, blood pressure usually increases gradually to pretreatment values within two to three days. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Metyrosine inhibits tyrosine hydroxylase, which catalyzes the first transformation in catecholamine biosynthesis, i.e., the conversion of tyrosine to dihydroxyphenylalanine (DOPA). Because the first step is also the rate-limiting step, blockade of tyrosine hydroxylase activity results in decreased endogenous levels of catecholamines and their synthesis. This consequently, depletes the levels of the catecholamines dopamine, adrenaline and noradrenaline in the body,usually measured as decreased urinary excretion of catecholamines and their metabolites. One main end result of the catecholamine depletion is a decrease in blood presure. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Well absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Little biotransformation, with catechol metabolites accounting for less than 1% of the administered dose. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Because the first step is also the rate-limiting step, blockade of tyrosine hydroxylase activity results in decreased endogenous levels of catecholamines, usually measured as decreased urinary excretion of catecholamines and their metabolites. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 3.4 to 3.7 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Signs of metyrosine overdosage include those central nervous system effects observed in some patients even at low dosages. At doses exceeding 2000 mg/day, some degree of sedation or feeling of fatigue may persist. Doses of 2000-4000 mg/day can result in anxiety or agitated depression, neuromuscular effects (including fine tremor of the hands, gross tremor of the trunk, tightening of the jaw with trismus), diarrhea, and decreased salivation with dry mouth. The acute toxicity of metyrosine was 442 mg/kg and 752 mg/kg in the female mouse and rat respectively. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Demser •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (-)-alpha-Methyl-L-tyrosine (–)-α-methyl-L-tyrosine (S)-alpha-Methyltyrosine (common) Methyltyrosine (common) Metirosin (common) Metirosina (common) Metirosine (common) Métirosine (common) Metirosinum (common) Metyrosine (common) α-methyl-L-p-tyrosine α-methyl-p-tyrosine α-methyl-para-tyrosine α-MPT

Do Abaloparatide and Minoxidil interact?

•Drug A: Abaloparatide •Drug B: Minoxidil •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Minoxidil is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of severe hypertension and in the topical treatment (regrowth) of androgenic alopecia in males and females and stabilisation of hair loss in patients with androgenic alopecia. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Minoxidil is an orally effective direct acting peripheral vasodilator that reduces elevated systolic and diastolic blood pressure by decreasing peripheral vascular resistance. Minoxidil is also used topically to treat androgenetic alopecia. Microcirculatory blood flow in animals is enhanced or maintained in all systemic vascular beds. In man, forearm and renal vascular resistance decline; forearm blood flow increases while renal blood flow and glomerular filtration rate are preserved. The predominant site of minoxidil action is arterial. Venodilation does not occur with minoxidil; thus, postural hypotension is unusual with its administration. The antihypertensive activity of minoxidil is due to its sulphate metabolite, minoxidil sulfate. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Minoxidil is thought to promote the survival of human dermal papillary cells (DPCs) or hair cells by activating both extracellular signal-regulated kinase (ERK) and Akt and by preventing cell death by increasing the ratio of BCl 2/Bax. Minoxidil may stimulate the growth of human hairs by prolonging anagen through these proliferative and anti-apoptotic effects on DPCs. Minoxidil, when used as a vasodilator, acts by opening adenosine triphosphate-sensitive potassium channels in vascular smooth muscle cells. This vasodilation may also improve the viability of hair cells or hair follicles. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Minoxidil is at least 90% absorbed from the GI tract in experimental animals and man. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Minoxidil does not bind to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Approximately 90% of the administered drug is metabolized, predominantly by conjugation with glucuronic acid at the N-oxide position in the pyrimidine ring, but also by conversion to more polar products. Known metabolites exert much less pharmacologic effect than minoxidil itself. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 4.2 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral LD 50 in rats has ranged from 1321-3492 mg/kg; in mice, 2456-2648 mg/kg. Side effects include cardiovascular effects associated with hypotension such as sudden weight gain, rapid heart beat, faintness or dizziness. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Loniten, Minox, Regoxidine, Rogaine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2,4-Diamino-6-piperidinopyrimidine 3-oxide 6-Piperidin-1-ylpyrimidine-2,4-diamine 3-oxide Minossidile (common) Minoxidil (common) Minoxidilum (common)

Do Abaloparatide and Moclobemide interact?

•Drug A: Abaloparatide •Drug B: Moclobemide •Severity: MODERATE •Description: Moclobemide may increase the orthostatic hypotensive activities of Abaloparatide. •Extended Description: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. •References: 1. Cockhill LA, Remick RA: Blood pressure effects of monoamine oxidase inhibitors--the highs and lows. Can J Psychiatry. 1987 Dec;32(9):803-8. [https://go.drugbank.com/articles/A36302] 2. Remick RA, Froese C: Monoamine oxidase inhibitors: clinical review. Can Fam Physician. 1990 Jun;36:1151-5. [https://go.drugbank.com/articles/A36361] 3. Delini-Stula A, Baier D, Kohnen R, Laux G, Philipp M, Scholz HJ: Undesirable blood pressure changes under naturalistic treatment with moclobemide, a reversible MAO-A inhibitor--results of the drug utilization observation studies. Pharmacopsychiatry. 1999 Mar;32(2):61-7. doi: 10.1055/s-2007-979193. [https://go.drugbank.com/articles/A36609] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of major depressive disorder and bipolar disorder. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): A selective, reversible inhibitor of monoamine oxidase (MAO) which increases the. Besides its presence in sympathetic nerves, there is an abundant evidence that MAO-A is localized in noradrenergic neurons in the locus coeruleus and MAO-B is closely associated with serotonergic neurons of the raphe nucleus. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The mechanism of action of moclobemide involves the selective, reversible inhibition of MAO-A. This inhibition leads to a decrease in the metabolism and destruction of monoamines in the neurotransmitters. This results in an increase in the monoamines, relieving depressive symptoms. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Well absorbed from the gastrointestinal tract (> 95%). The presence of food reduces the rate but not the extent of absorption. Hepatic first-pass metabolism reduces bioavailability to about 56% following administration of one dose, but increases to 90% with steady-state dosing as a result of saturation of the first pass effect. Peak plasma concentrations are reached within 0.3 - 1 hours following oral administration with a terminal half-life of 1.6h. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 1-1.5 L/Kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Approximately 50% (primarily to albumin) •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Moclobemide is almost completely metabolized in the liver by Cytochrome P450 2C19 and 2D6. Moclobemide is a substrate of CYP2C19. Although it acts as an inhibitor of CYP1A2, CYP2C19, and CYP2D6. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Moclobemide is almost completely renally excreted. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 1-2 hours (4 hours in cirrhotic patients); metabolites are renally excreted •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Clearance of 30-78 L/h, mainly excreted in urine. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD50 (mouse) is 730mg/kg and LD50 (rat) is 1,300mg/kg. Signs of toxicity include hypertension, drowsiness, dizziness, confusion, tremors, headache, agitation, muscle rigidity and seizures. The effects of moclobemide alone in overdose are negligible, even with high volume ingestion. However, moclobemide overdose with a serotonergic agent (even in small, therapeutic doses) can cause severe serotonin toxicity. The elimination half-life is prolonged by two to four times in overdose, compared with that found in healthy volunteers given therapeutic doses. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Manerix •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 4-Chlor-N-(2-morpholinoethyl)benzamid Moclobemid (common) Moclobemida (common) Moclobemide (common) Moclobemidum (common) p-Chloro-N-(2-morpholinoethyl)benzamide

Do Abaloparatide and Moexipril interact?

•Drug A: Abaloparatide •Drug B: Moexipril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Moexipril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Moexipril is a non-sulfhydryl containing precursor of the active angiotensin-converting enzyme (ACE) inhibitor moexiprilat. It is used to treat high blood pressure (hypertension). It works by relaxing blood vessels, causing them to widen. Lowering high blood pressure helps prevent strokes, heart attacks and kidney problems. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Moexipril is a prodrug for moexiprilat, which inhibits ACE in humans and animals. The mechanism through which moexiprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes the conversion of the inactive decapeptide angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor that also stimulates aldosterone secretion by the adrenal cortex and provides negative feedback on renin secretion. ACE is identical to kininase II, an enzyme that degrades bradykinin, an endothelium-dependent vasodilator. Moexiprilat is about 1000 times as potent as moexipril in inhibiting ACE and kininase II. Inhibition of ACE results in decreased angiotensin II formation, leading to decreased vasoconstriction, increased plasma renin activity, and decreased aldosterone secretion. The latter results in diuresis and natriuresis and a small increase in serum potassium concentration (mean increases of about 0.25 mEq/L were seen when moexipril was used alone). Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of moexipril remains to be elucidated. Although the principal mechanism of moexipril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect on blood pressure even in apparent low-renin hypertension. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Moexipril is incompletely absorbed, with bioavailability as moexiprilat of about 13% compared to intravenous (I.V.) moexipril (both measuring the metabolite moexiprilat), and is markedly affected by food, which reduces C max and AUC by about 70% and 40%, respectively, after the ingestion of a low-fat breakfast or by 80% and 50%, respectively, after the ingestion of a high-fat breakfast. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 183 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Moexiprilat is approxomately 50% protein bound. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Rapidly converted to moexiprilat, the active metabolite. Conversion to the active metabolite is thought to require carboxyesterases and is likely to occur in organs or tissues, other than the gastrointestinal tract, in which carboxyesterases occur. The liver is thought to be one site of conversion, but not the primary site. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Moexiprilat undergoes renal elimination. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Moexipril elimination half-life is approximately 1 hour. Moexiprilat elimination half-life is 2 to 9 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 441 mL/min •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Human overdoses of moexipril have not been reported. In case reports of overdoses with other ACE inhibitors, hypotension has been the principal adverse effect noted. Single oral doses of 2 g/kg moexipril were associated with significant lethality in mice. Rats, however, tolerated single oral doses of up to 3 g/kg. Common adverse effects include cough, dizziness, diarrhea, flu syndrome, fatigue, pharyngitis, flushing, rash, and myalgia •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Univasc •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Morphine interact?

•Drug A: Abaloparatide •Drug B: Morphine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Morphine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Morphine is used for the management of chronic, moderate to severe pain. Opiods, including morphine, are effective for the short term management of pain. Patients taking opioids long term may need to be monitored for the development of physical dependence, addiction disorder, and drug abuse. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Morphine binding to opioid receptors blocks transmission of nociceptive signals, signals pain-modulating neurons in the spinal cord, and inhibits primary afferent nociceptors to the dorsal horn sensory projection cells. Morphine has a time to onset of 6-30 minutes. Excess consumption of morphine and other opioids can lead to changes in synaptic neuroplasticity, including changes in neuron density, changes at postsynaptic sites, and changes at dendritic terminals. Intravenous morphine's analgesic effect is sex dependent. The EC 50 in men is 76ng/mL and in women is 22ng/mL. Morphine-6-glucuronide is 22 times less potent than morphine in eliciting pupil constriction. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Morphine-6-glucuronide is responsible for approximately 85% of the response observed by morphine administration. Morphine and its metabolites act as agonists of the mu and kappa opioid receptors. The mu-opioid receptor is integral to morphine's effects on the ventral tegmental area of the brain. Morphine's activation of the reward pathway is mediated by agonism of the delta-opioid receptor in the nucleus accumbens, while modification of the respiratory system and addiction disorder are mediated by agonism of the mu-opioid receptor. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Morphine is absorbed in the alkaline environments of the upper intestine and rectal mucosa. The bioavailability of morphine is 80-100%. There is significant first-pass metabolism, therefore oral doses are 6 times larger than parenteral doses to achieve the same effect. Morphine reaches steady-state concentrations after 24-48 hours. Parenteral morphine has a T max of 15 minutes and oral morphine has a T max of 90 minutes, with a C max of 283nmol/L. The AUC of morphine is 225-290nmol*h/L. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of morphine is 5.31L/kg. Morphine-6-glucuronide has a volume of distribution of 3.61L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Morphine is 35% protein bound, the metabolite morphine-3-glucuronide is 10% protein bound, and morphine-6-glucuronide is 15% protein bound. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Morphine is 90% metabolized by glucuronidation by UGT2B7 and sulfation at positions 3 and 6. Morphine can also be metabolized to codeine, normorphine, and morphine ethereal sulfate. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 70-80% of an administered dose is excreted within 48 hours. Morphine is predominantly eliminated in the urine with 2-10% of a dose recovered as the unchanged parent drug. 7-10% of a dose of morphine is eliminated in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Morphine has a half life of 2-3 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The apparent clearance of intravenous or subcutaneous morphine is 1600 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The LD 50 is 0.78µg/mL in males and 0.98µg/mL in females. Patients experiencing an overdose present with respiratory depression, somnolence, skeletal muscle flaccidity, cold and clammy skin, miosis, and mydriasis. Symptoms of overdose can progress to pulmonary edema, bradycardia, hypotension, cardiac arrest, and death. Treat overdose with symptomatic and supportive treatment which may include the use of oxygen, vasopressors, and naloxone. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Arymo, Avinza, Doloral, Duramorph, Embeda, Infumorph, Kadian, M-ediat, M-eslon, MSIR, Mitigo, Ms Contin, Statex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (−)-morphine (5alpha,6alpha)-17-methyl-7,8-didehydro-4,5-epoxymorphinan-3,6-diol (5alpha,6alpha)-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol (5R,6S,9R,13S,14R)-4,5-epoxy-N-methyl-7-morphinen-3,6-diol (5α,6α)-17-methyl-7,8-didehydro-4,5-epoxymorphinan-3,6-diol (5α,6α)-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol (7R,7AS,12bs)-3-methyl-2,3,4,4a,7,7a-hexahydro-1H-4,12-methano[1]benzofuro[3,2-e]isoquinoline-7,9-diol Anhydrous morphine Morfina (common) Morphia (common) Morphin (common) Morphine (common) Morphinum (common) Morphium (common)

Do Abaloparatide and Moxonidine interact?

•Drug A: Abaloparatide •Drug B: Moxonidine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Moxonidine. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of mild to moderate essential or primary hypertension. Effective as most first-line antihypertensives when used as monotherapy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Antihypertensive agent whose site of action is the Central Nervous System (CNS), specifically involving interactions with I1- imidazoline and alpha-2-adrenergic rececptors within the rostral ventrolateral medulla (RSV). •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Stimulation of central alpha 2-adrenergic receptors is associated with sympathoadrenal suppression and subsequent reduction of blood pressure. As this class was further explored it was discovered that sympathoadrenal activity can also be suppressed by a second pathway with a newly discovered drug target specific to imidazolines. Specifically, moxonidine binds the imidazoline receptor subtype 1 (I1) and to a lesser extent αlpha-2-adrenoreceptors in the RSV causing a reduction of sympathetic activity, reducing systemic vascular resistance and thus arterial blood pressure. Moreover, since alpha-2-adrenergic receptors are considered the primary molecular target that facilitates the most common side effects of sedation and dry mouth that are elicited by most centrally acting antihypertensives, moxonidine differs from these other centrally acting antihypertensives by demonstrating only low affinity for central alpha-2-adrenoceptors compared to the aforementioned I1-imidazoline receptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): 90% of an oral dose is absorbed with negligible interference from food intake or first pass metabolism, resulting in a high bioavailability of 88%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 1.8±0.4L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): About 10% of moxonidine is bound to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Biotransformation is unimportant with 10-20% of moxonidine undergoing oxidation reactions to the primary 4,5-dehydromoxonidine metabolite and a guanidine derivative by opening of the imidazoline ring. The antihypertensive effects of these 4,5-dehydromoxonidine and guanidine metabolites are only 1/10 and 1/100 the effect of moxonidine. Oxidation on either the methyl group (pyrimidine ring) or on the imidazole ring of moxonidine results in the formation of the hydroxylmethyl moxonidine metabolite or the hydroxy moxonidine metabolite. The hydroxy moxonidine metabolite can be further oxidized to the dihydroxy metabolite or it can lose water to form the dehydrogenated moxonidine metabolite, which itself can be further oxidized to form an N-oxide. Aside from these Phase I metabolites, Phase II metabolism of moxonidine is also evident with the presence of a cysteine conjugate metabolite minus chlorine. Nevertheless, the identification of the hydroxy moxonidine metabolite with a high level of dehydrogenated moxonidine metabolite in human urine samples suggests that dehydrogenation from the hydroxy metabolite to the dehydrogenated moxonidine metabolite represents the primary metabolic pathway in humans. The cytochromes P450 responsible for the metabolism of moxonidine in humans have not yet been determined. Ultimately, the parent moxonidine compound was observed to be the most abundant component in different biological matrices of urinary excretion samples, verifying that metabolism only plays a modest role in the clearance of moxonidine in humans. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Elimination is nearly entirely via the kidneys with a majority (50 -75%) of overall moxonidine being eliminated unchanged through renal excretion. Ultimately, more than 90% of a dose is eliminated by way of the kidneys within the first 24 hours after administration, with only approximately 1% being eliminiated via faeces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Plasma elimination half life is 2.2 - 2.3 hours while renal elimination half life is 2.6-2.8 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Administered twice daily due to short half life. However, lower dosage adjustments and close monitoring is necessary in elderly and renal impairment patients due to reduced clearance. In particular, the exposure AUC can increase by about 50% following a single dose and at steady state in elderly patients and moderately impaired renal function with GFR between 30-60 mL/min can cause AUC increases by 85% and decreases in clearence to 52 %. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Contraindicated due to known hypersensitivity to an ingredient (Physiotens tablets contain lactose), heart failure, severe renal impairment, < 16 years old, >75 years old, bradycardia, severe bradyarrhythmia, sick sinus syndrome, second or third degree atrioventricular block, malignant arrhythmias. Used with caution in patients with history of severe coronary artery disease (CAD), unstable angina, angioneurotic edema. Pregnancy Category B3:Avoid use during pregnancy (inadequate data in pregnant woman) and lactation (maternal blood stream transfer to breast milk shown) unless benefit clearly justifies risk. Lack of specific therapeutic experience in cases of intermittent claudication, Raynaud's disease, Parkinson's disease, epileptic disorders, gluacoma, and depression suggest moxonidine should not be used in such instances. Carcinogenicity and genotoxicity does not appear significant. Concurrent administration of other hypotensives or sedative and hypnotics can enhance the hypotensive effect and intensify sedation respectively. Avoid concurrent Tricyclic Antidepressant (TCA) use to avoid reduction of monoxidine efficacy. Generally well tolerated with dry mouth and headache the most common adverse effects Symptoms of overdose correlate with pharmacodynamic properties:hypotension, sedation, orthostatic dysregulation, bradycardia, dry mouth with no specific counter-treatment known. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (2R,4R)-1-[(2S)-5-[(aminoiminomethyl)amino]-1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl-8- quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid Moxonidina (common) Moxonidine (common) Moxonidinum (common)

Do Abaloparatide and Nabilone interact?

•Drug A: Abaloparatide •Drug B: Nabilone •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Nabilone is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Nabilone is indicated for the treatment of the nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. This restriction is required because a substantial proportion of any group of patients treated with Nabilone can be expected to experience disturbing psychotomimetic reactions not observed with other antiemetic agents. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Nabilone is a cannabinoid with therapeutic uses. It is an analog of dronabinol (also known as tetrahydrocannabinol or THC), the psychoactive ingredient in cannabis. Although structurally distinct from THC, nabilone mimics THC's structure and pharmacological activity through weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors, however it is considered to be twice as active as Δ⁹-THC. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Nabilone is an orally active synthetic cannabinoid which, like other cannabinoids, has complex effects on the central nervous system (CNS). It has been suggested that the antiemetic effect of nabilone is caused by interaction with the cannabinoid receptor system, i.e., the CB (1) receptor, which is a component of the endocannabinoid system of the body. The endocannabinoid system is widely distributed throughout the central and peripheral nervous system (via the Cannabinoid Receptors CB1 and CB2) and plays a role in many physiological processes such as inflammation, cardiovascular function, learning, pain, memory, stress and emotional regulation, and the sleep/wake cycle among many others. CB1 receptors are found in both the central and peripheral nervous system, and are most abundant in the hippocampus and amygdala, which are the areas of the brain responsible for short-term memory storage and emotional regulation. CB2 receptors are mainly located in the peripheral nervous system and can be found on lymphoid tissue where they are involved in regulation of immune function. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Nabilone appears to be completely absorbed from the human gastrointestinal tract when administered orally. Following oral administration of a 2 mg dose of radiolabeled nabilone, peak plasma concentrations of approximately 2 ng/mL nabilone and 10 ng equivalents/mL total radioactivity are achieved within 2.0 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution of nabilone is about 12.5 L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. Two metabolic pathways have been suggested. The major pathway probably involves the direct oxidation of Nabilone to produce hydroxylic and carboxylic analogues. These compounds are thought to account for the remaining plasma radioactivity when carbinol metabolites have been extracted. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The route and rate of the elimination of nabilone and its metabolites are similar to those observed with other cannabinoids, including delta-9-THC (dronabinol). When nabilone is administered intravenously, the drug and its metabolites are eliminated mainly in the feces (approximately 67%) and to a lesser extent in the urine (approximately 22%) within 7 days. Of the 67% recovered from the feces, 5% corresponded to the parent compound and 16% to its carbinol metabolite. Following oral administration about 60% of nabilone and its metabolites were recovered in the feces and about 24% in urine. Therefore, it appears that the major excretory pathway is the biliary system. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The plasma half-life (T1/2) values for nabilone and total radioactivity of identified and unidentified metabolites are about 2 and 35 hours, respectively. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include difficulty in breathing, hallucinations, mental changes (severe), nervousness or anxiety (severe). Monkeys treated with Nabilone at doses as high as 2mg/kg/day for a year experienced no significant adverse events. This result contrasts with the finding in a planned 1-year dog study that was prematurely terminated because of deaths associated with convulsions in dogs receiving as little as 0.5mg/kg/day. The earliest deaths, however, occurred at 56 days in dogs receiving 2mg/kg/day. The unusual vulnerability of the dog is not understood; it is hypothesised, however, that the explanation lies in the fact that the dog differs markedly from other species (including humans) in its metabolism of Nabilone. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cesamet •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Nadolol interact?

•Drug A: Abaloparatide •Drug B: Nadolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Nadolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Nadolol is indicated to treat angina pectoris and hypertension. Another product formulated with bendroflumethiazide is indicated to treat hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Nadolol is a nonselective beta adrenal receptor blocker that is used to lower blood pressure. It has a long duration of action as it is usually taken once daily and a wide therapeutic index as patients start at doses of 40mg daily but may be increased to doses as high as 240mg daily. Patients taking nadolol should not aburptly stop taking it as this may lead to exacerbation of ischemic heart disease. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Although nadolol is described as a non selective beta blocker, it does not interact with beta 3 adrenal receptors. Antagonism of beta-1 and beta-2 adrenoceptors in the heart inhibits cyclic AMP and its signalling pathway, decreasing the strength and speed of contractions as well as the speed of relaxation and conduction. Antagonism of beta-2 adrenoceptors in the smooth muscle cells of the vasculature inhibits their relaxation, leading to an increase in peripheral vascular resistance and reducing the risk of severe hypotension. The increase in peripheral vascular resistance may contribute to the decrease in insulin sensitivity associated with nadolol use. Antagonism of beta-1 adrenoceptors in the juxtaglomerular apparatus of the kidney inhibits the release of renin, and therefore angiotensin II mediated vasoconstriction, aldosterone mediated water retention, and the release of epinephrine. Antagonism of beta-2 adrenoceptors in the liver and skeletal muscle inhibits glycogenolysis, in the lungs prevents bronchodilation, and in the pancrease inhibits insulin release. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Oral doses of nadolol are approximately 30% absorbed. In healthy subjects, nadolol has a T max of 2.7h with a C max or 69±15ng/mL following a 60mg oral dose and 132±27ng/mL after a 120mg oral dose. The AUC following a 60mg oral dose was 1021ng*h/mL and following a 120mg oral dose was 1913±382ng*h/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): In healthy subjects, the volume of distribution of nadolol is 147-157L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Nadolol is approximately 30% bound to plasma protein. Nadolol binds to alpha-1-acid glycoprotein in plasma. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Nadolol is not metabolized by the liver in humans. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Nadolol is not metabolized in the liver and excreted mainly in the urine. In healthy subjects, following intravenous dosing, 60% of a dose is eliminated in the urine and 15% in the feces after 72 hours. The remainder of the dose is expected to be eliminated in the feces afterwards. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half life of nadolol is 20 to 24 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): In healthy subjects, the total body clearance of nadolol is 219-250mL/min and the renal clearance is 131-150mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 in mice is 4500mg/kg. Patients experiencing an overdose may present with bradycardia, cardiac failure, hypotension, and bronchospasm. An overdose may be treated with atropine for bradycardia, digitalis and diuretics for cardiac failure, vasopressors for hypotension, and beta-2 stimulants for bronchospasms, as well as gastric lavage and hemodialysis. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Corgard •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Nebivolol interact?

•Drug A: Abaloparatide •Drug B: Nebivolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Nebivolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Nebivolol is indicated to treat hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Nebivolol is a selective beta-1 adrenergic receptor antagonist that decreases vascular resistance, increases stroke volume and cardiac output, and does not negatively affect left ventricular function. It has a long duration of action as effects can be seen 48 hours after stopping the medication and a wide therapeutic window as patients generally take 5-40mg daily. Patients should not abruptly stop taking this medication as this may lead to exacerbation of coronary artery disease. Diabetic patients should monitor their blood glucose levels as beta blockers may mask signs of hypoglycemia. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Nebivolol is a highly selective beta-1 adrenergic receptor antagonist with weak beta-2 adrenergic receptor antagonist activity. Blocking beta-1 adrenergic receptors by d-nebivolol leads to decreased resting heart rate, exercise heart rate, myocardial contracility, systolic blood pressure, and diastolic blood pressure. The selectivity of d-nebivolol limits the magnitude of beta blocker adverse effects in the airways or relating to insulin sensitivity. Nebivolol also inhibits aldosterone, and beta-1 antagonism in the juxtaglomerular apparatus also inhibits the release of renin. Decreased aldosterone leads to decreased blood volume, and decreased renin leads to reduced vasoconstriction. l-nebivolol is responsible for beta-3 adrenergic receptor agonist activity that stimulates endothelial nitric oxide synthase, increasing nitric oxide levels; leading to vasodilation, decreased peripheral vascular resistance, increased stroke volume, ejection fraction, and cardiac output. The vasodilation, reduced oxidative stress, and reduced platelet volume and aggregation of nebivolol may lead to benefits in heart failure patients. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The absorption of nebivolol is not affected by food. Nebivolol has a T max of 1.5-4 hours. Bioavailability can range from 12-96% for extensive to poor CYP2D6 metabolizers. For a 20mg dose, d-nebivolol has a C max of 2.75±1.55ng/mL, l-nebivolol has a C max of 5.29±2.06ng/mL, both enantiomers have a C max of 8.02±3.47ng/mL, and nebivolol glucuronides have a C max of 68.34±44.68ng/mL. For a 20mg dose, d-nebivolol has an AUC of 13.78±15.27ng*h/mL, l-nebivolol has an AUC of 27.72±15.32ng*h/mL, both enantiomers have an AUC of 41.50±29.76ng*h/mL, and nebivolol glucuronides have an AUC of 396.78±297.94ng*h/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): For a 20mg dose, d-nebivolol has an apparent volume of distribution of 10,290.81±3911.72L, l-nebivolol has an apparent volume of distribution of 8,066.66±4,055.50L, and both enantiomers together have a volume of distribution of 10,423.42±6796.50L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Nebivolol is 98% bound to plasma proteins, mostly to serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Nebivolol is metabolized mainly by glucuronidation and CYP2D6 mediated hydroxylation. Metabolism involves n-dealkylation, hydroxylation, oxidation, and glucuronidation. Aromatic hydroxyl and acyclic oxide metabolites are active, while n-dealkylated and glucuronides are inactive. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): In extensive CYP2D6 metabolizers, 38% is eliminated in the urine and 44% in the feces. In poor CYP2D6 metabolizers, 67% is eliminated in the urine and 13% in the feces. <1% of a dose is excreted as the unmetabolized drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): d-nebivolol has a half life of 12 hours in CYP2D6 extensive metabolizers and 19 hours in poor metabolizers. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): For a 20mg dose, the clearance of d-nebivolol is 1241.63±749.77L/h, l-nebivolol is 435.53±180.93L/h, and both enantiomers is 635.31±300.25L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Patients experiencing an overdose may present with bradycardia, hypotension, cardiac failure, dizziness, hypoglycemia, fatigue, vomiting, bronchospasm and heart block. Treat overdose with general supportive measures including intravenous atropine for bradycardia, vasopressors and intravenous fluids for hypotension, isoproterenol infusion for heart block, digitalis glycosides and diuretics for congestive heart failure, bronchodilators for bronchospasm, and intravenous glucose for hypoglycemia. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Bystolic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Nicardipine interact?

•Drug A: Abaloparatide •Drug B: Nicardipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Nicardipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used for the management of patients with chronic stable angina and for the treatment of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Nicardipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Nicardipine is similar to other peripheral vasodilators. Nicardipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, nicardipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): While nicardipine is completely absorbed, it is subject to saturable first pass metabolism and the systemic bioavailability is about 35% following a 30 mg oral dose at steady state. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 8.3 L/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): >95% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Nicardipine HCl is metabolized extensively by the liver. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Nicardipine has been shown to be rapidly and extensively metabolized by the liver. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 8.6 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 0.4 L/hr∙kg [Following infusion] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral LD 50 Rat = 184 mg/kg, Oral LD 50 Mouse = 322 mg/kg •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cardene •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Nicorandil interact?

•Drug A: Abaloparatide •Drug B: Nicorandil •Severity: MINOR •Description: Nicorandil may increase the hypotensive activities of Abaloparatide. •Extended Description: Nicorandil is an agent that induces the relaxation of vascular smooth muscle, and is associated with a risk for developing severe hypotension as an adverse event. There is also the possibility that nicorandil may potentiate the hypotensive effects of other vasodilators. •References: 1. Ishizuka N, Saito K, Akima M, Matsubara S, Saito M: Hypotensive interaction of sildenafil and nicorandil in rats through the cGMP pathway but not by K(ATP) channel activation. Jpn J Pharmacol. 2000 Nov;84(3):316-24. [https://go.drugbank.com/articles/A37409] 2. Tarkin JM, Kaski JC: Vasodilator Therapy: Nitrates and Nicorandil. Cardiovasc Drugs Ther. 2016 Aug;30(4):367-378. doi: 10.1007/s10557-016-6668-z. [https://go.drugbank.com/articles/A37410] 3. Humphrey SJ: Cardiovascular and pharmacokinetic interactions between nicorandil and adjunctive propranolol, atenolol or diltiazem in conscious dogs. Methods Find Exp Clin Pharmacol. 1998 Nov;20(9):779-91. [https://go.drugbank.com/articles/A37415] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Indicated for the prevention and treatment of chronic stable angina pectoris and reduction in the risk of acute coronary syndromes. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Nicorandil is a potassium channel opener with nitrovasodilator (NO donor) actions, making it both an arterial and a venous dilator. It causes sustained dilation of both the arterial resistance and conductive vessels that increases coronary blood flow, however the effect of the drug on coronary arteries does not involve the coronary steal phenomenon. Activation of potassium channels lead to hyperpolarization of the smooth muscle cells, followed by arterial dilation and afterload reduction. Nicorandil is shown to increase pooling in the capacitance vessels with a decrease in preload through relaxing the venous vascular system. Overall, improved blood flow and reduced infarct size are achieved through reduction of end-diastolix pressure and decreased extravascular component of vascular resistance. Open studies showed the effectiveness of nicorandil treatment on various types of angina pectoris. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Nicorandil mediates its therapeutic efficacy via two main mechanisms. Nicorandil is an activator and opener of ATP-sensitive (ATP-dependent) potassium channels (KATP channels) that are composed of Kir6.x-type subunits and sulfonylurea receptor (SUR) subunits. Nicorandil binding sites are located in the sulfonylurea receptor 2 (SUR2) in the ATP-sensitive potassium channel, which are regulatory subunits of the channel that exhibit an ATPase activitiy. There are 2 types of SUR2 subunits (2A/2B) that have identical nucleotide binding domains (NBD), where SUR2A is more predominantly expressed in skeletal and cardiac myocytes and SUR2B in smooth muscle cells. Nicorandil more potently activates SUR2B/Kir6.2 than SUR2A/Kir6.2 channels to cause hyperpolarization. ATP-NBD1 interaction influences the channel signalling by nicorandil, and the response of the channel to nicorandil is also facilitated and heightened by the interaction of ATP or ADP with NBD2. Potentiated activity of ATP-sensitive channels have cardioprotective role by limiting the duration of action potentials and preventing intraceullar calcium overload. This attenuates cellular injury by preserving cellular energetics and ultimately cell survival. KATP channel-dependent membrane hyperpolarization can also lead to vasodilation via reduction in Ca2+ influx through the voltage-gated Ca2+ channels and regulation of intracellular Ca2+ mobilization in smooth muscle cells. Nicorandil contain a nitrate moiety in its structure, making it a good dilator of vascular smooth muscle like other nitroglycerin esters. Direct relaxation of venous vascular system arises from NO-donor mediated stimulation of guanylyl cyclase and increased levels of intracellular cyclic GMP (cGMP). Elevated levels of cGMP contributes to the total relaxing effect of nicorandil at higher concentrations of the drug. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following oral administration, nicorandil is well absorbed from the gastrointestinal tract with the oral bioavailability of 75% with the maximum peak plasma concentration (Cmax) reached within 30-60 minutes. The mean Cmax is Cmax then is approximately 300 ng/ml. Steady-state plasma concentrations of nicorandil usually are reached within approximately 96-120 h after twice daily dosing (10 or 20mg). •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): After oral (and i.v.) administration of the drug, the apparent volume of distribution is approximately 1.0-1.4 L/kg body weight. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Nicorandil is about 25% bound to human albumin and other plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Nicorandil undergoes extensive hepatic metabolism. The main biotransformation pathways of nicorandil are denitration, followed by subsequent nicotinamide metabolism. The main pharmacologically inactive denitrated metabolite 2-nicotinamidoethanol can be detected in the urine. The derivatives formed from the nicotinamide metabolism of denitrated products are nicotinuric acid, nicotinamide, N-methylnicotinamide and nicotinic acid. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The main route of elimination is the kidney with more than 60% of the administered dose was eliminated in the urine 24 hours after dosing. Only approximately 1% of nicorandil is excreted unchanged in the urine, and the remaining compounds are mainly the denitrated metabolite (9%) and its derivatives (e.g. nicotinuric acid 6%, nicotinamide 1%, N-methylnicotinamide < 1% and nicotinic acid < 1%). Less than 2% of administered dose is excreted through the biliary system. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half life is approximately 1 hour. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The total body clearance is approximately 1.15 L/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Common adverse effects include lethargy, back pain, chest pain, infection, feeling of weakness. In the cardiovascular system, hypotension, increased heart rate in higher doses, palpitations, worsened angina pectoris and vasodilation/flush may be observed. Dyspepsia, nausea, and vomiting may occur as gastrointestinal disorders. Headaches may arise from vasodilation. Other common side effects include myalgia, bronchitis, dyspnoea, and respiratory disorder. Nicorandil does not affect fertility of male or female rats, and shows no potential in carcinogenic, mutagenic or genotoxic studies. Oral LD50 values in mouse, rat and dog are 626 mg/kg, 1220 mg/kg and 62.5 mg/kg, respectively. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-Nicotinamidoethyl nitrate N-(2-Hydroxyethyl)nicotinamide nitrate N-(2-Hydroxyethyl)nicotinamide nitrate (ester) Nicorandil (common) Nicorandilum (common)

Do Abaloparatide and Nifedipine interact?

•Drug A: Abaloparatide •Drug B: Nifedipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Nifedipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Nifedipine capsules are indicated to treat vasospastic angina and chronic stable angina. Extended release tablets are indicated to treat vasospastic angina, chronic stable angina, and hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Nifedipine is an inhibitor of L-type voltage gated calcium channels that reduces blood pressure and increases oxygen supply to the heart. Immediate release nifedipine's duration of action requires dosing 3 times daily. Nifedipine dosing is generally 10-120mg daily. Patients should be counselled regarding the risk of excessive hypotension, angina, and myocardial infarction. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Nifedipine blocks voltage gated L-type calcium channels in vascular smooth muscle and myocardial cells. This blockage prevents the entry of calcium ions into cells during depolarization, reducing peripheral arterial vascular resistance and dilating coronary arteries. These actions reduce blood pressure and increase the supply of oxygen to the heart, alleviating angina. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Sublingual dosing leads to a C max of 10ng/mL, with a T max of 50min, and an AUC of 25ng*h/mL. Oral dosing leads to a C max of 82ng/mL, with a T max of 28min, and an AUC of 152ng*h/mL. Nifedipine is a Biopharmaceutics Classification System Class II drug, meaning it has low solubility and high intestinal permeability. It is almost completely absorbed in the gastrointestinal tract but has a bioavilability of 45-68%, partly due to first pass metabolism. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The steady state volume of distribution of nifedipine is 0.62-0.77L/kg and the volume of distribution of the central compartment is 0.25-0.29L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Nifedipine is 92-98% protein bound in serum. Nifedipine is 97±12% bound in a 40g/L solution of pure albumin. Nifedipine is 51.4±5.9% protein bound in a 50mg/100mL solution of alpha-1-acid glycoprotein, and 75.5±3.5% protein bound in a 150mg/mL solution. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Nifedipine is predominantly metabolized by CYP3A4. Nifedipine is predominantly metabolized to 2,6-dimethyl-4-(2-nitrophenyl)-5-methoxycarbonyl-pyridine-3-carboxylic acid, and then further metabolized to 2-hydroxymethyl-pyridine carboxylic acid. Nifedipine is also minorly metabolized to dehydronifedipine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Nifedipine is 60-80% recovered in the urine as inactive water soluble metabolites, and the rest is eliminated in the feces as metabolites. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half life of nifedipine is approximately 2 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The total body clearance of nifedipine is 450-700mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 in rats is 1022mg/kg and in mice is 202mg/kg. Patients experiencing an overdose may present with hypotension, sinus node dysfunction, atrioventricular node dysfunction, and reflex tachycardia. Overdose may be managed by monitoring cardiovascular and respiratory function; elevating extremities; and administering vasopressors, fluids, and calcium infusions. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Adalat, Afeditab CR, Nifediac, Nifedical, Procardia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 4-(2'-Nitrophenyl)-2,6-dimethyl-1,4-dihydropyridin-3,5-dicarbonsäuredimethylester Nifedipine (common) Nifedipino (common) Nifedipinum (common)

Do Abaloparatide and Nilvadipine interact?

•Drug A: Abaloparatide •Drug B: Nilvadipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Nilvadipine. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the management of vasospastic angina, chronic stable angina and hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Nilvadipine is similar to other dihydropyridines including amlodipine, felodipine, isradipine, and nicardipine. Nilvadipine is used to treat Prinzmetal's angina, hypertension, and other vascular disorders such as Raynaud's phenomenon. By blocking the calcium channels, Nifedipine inhibits the spasm of the coronary artery and dilates the systemic arteries, results in a increase of myocardial oxygen supply and a decrease in systemic blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Nilvadipine inhibits the influx of extracellular calcium through myocardial and vascular membrane pores by physically plugging the channel. The decrease in intracellular calcium inhibits the contractile processes of smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Nimodipine interact?

•Drug A: Abaloparatide •Drug B: Nimodipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Nimodipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For use as an adjunct to improve neurologic outcome following subarachnoid hemorrhage (SAH) from ruptured intracranial berry aneurysms by reducing the incidence and severity of ischemic deficits. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Nimodipine belongs to the class of pharmacological agents known as calcium channel blockers. Nimodipine is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured congenital aneurysms who are in good neurological condition post-ictus (e.g., Hunt and Hess Grades I-III). The contractile processes of smooth muscle cells are dependent upon calcium ions, which enter these cells during depolarization as slow ionic transmembrane currents. Nimodipine inhibits calcium ion transfer into these cells and thus inhibits contractions of vascular smooth muscle. In animal experiments, nimodipine had a greater effect on cerebral arteries than on arteries elsewhere in the body perhaps because it is highly lipophilic, allowing it to cross the blood brain barrier. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Although the precise mechanism of action is not known, nimodipine blocks intracellular influx of calcium through voltage-dependent and receptor-operated slow calcium channels across the membranes of myocardial, vascular smooth muscle, and neuronal cells. By specifically binding to L-type voltage-gated calcium channels, nimodipine inhibits the calcium ion transfer, resulting in the inhibition of vascular smooth muscle contraction. Evidence suggests that the dilation of small cerebral resistance vessels, with a resultant increase in collateral circulation, and/or a direct effect involving the prevention of calcium overload in neurons may be responsible for nimodipine's clinical effect in patients with subarachnoid hemorrhage. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): In humans, nimodipine is rapidly absorbed after oral administration, and peak concentrations are generally attained within one hour. Bioavailability is 100% following intravenous administration and 3-30% following oral administration due to extensive first-pass metabolism. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 95% bound to plasma protein •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic metabolism via CYP 3A4. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Nimodipine is eliminated almost exclusively in the form of metabolites and less than 1% is recovered in the urine as unchanged drug. Numerous metabolites, all of which are either inactive or considerably less active than the parent compound, have been identified. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 1.7-9 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdosage would be expected to be related to cardiovascular effects such as excessive peripheral vasodilation with marked systemic hypotension. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Nimotop, Nymalize •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-β-methoxyethyl ester 5-isopropyl ester isopropyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate isopropyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate Nimodipine (common) Nimodipino (common) Nimodipinum (common)

Do Abaloparatide and Nisoldipine interact?

•Drug A: Abaloparatide •Drug B: Nisoldipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Nisoldipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Nisoldipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Nisoldipine is similar to other peripheral vasodilators. Nisoldipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Nisoldipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Relatively well absorbed into the systemic circulation with 87% of the radiolabeled drug recovered in urine and feces. The absolute bioavailability of nisoldipine is about 5%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 99% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Pre-systemic metabolism in the gut wall, and this metabolism decreases from the proximal to the distal parts of the intestine. Nisoldipine is highly metabolized; 5 major urinary metabolites have been identified. The major biotransformation pathway appears to be the hydroxylation of the isobutyl ester. A hydroxylated derivative of the side chain, present in plasma at concentrations approximately equal to the parent compound, appears to be the only active metabolite and has about 10% of the activity of the parent compound. Cytochrome P450 enzymes are believed to play a major role in the metabolism of nisoldipine. The particular isoenzyme system responsible for its metabolism has not been identified, but other dihydropyridines are metabolized by cytochrome P450 IIIA4. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Although 60-80% of an oral dose undergoes urinary excretion, only traces of unchanged nisoldipine are found in urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 7-12 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Sular •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): isobutyl methyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Nisoldipin (common) Nisoldipina (common) Nisoldipine (common) Nisoldipino (common) Nisoldipinum (common)

Do Abaloparatide and Nitrendipine interact?

•Drug A: Abaloparatide •Drug B: Nitrendipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Nitrendipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of mild to moderate hypertension •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Nitrendipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Nitrendipine is similar to other peripheral vasodilators. Nitrendipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Nitrendipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): > 99% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethyl methyl ester Nitrendipine (common) Nitrendipino (common) Nitrendipinum (common)

Do Abaloparatide and Nitric Oxide interact?

•Drug A: Abaloparatide •Drug B: Nitric Oxide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Nitric Oxide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of term and near-term (>34 weeks) neonates with hypoxic respiratory failure •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, Nitric oxide improves oxygenation (as indicated by significant increases in PaO2). Nitric oxide appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better entilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Nitric oxide is a compound produced by many cells of the body. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide produces pulmonary vasodilation. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Nitric oxide is absorbed systemically after inhalation. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): via pulmonary capillary bed •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for >70% of the nitric oxide dose inhaled. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 2–6 seconds •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Inomax, Kinox, Noxivent •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Nitroglycerin interact?

•Drug A: Abaloparatide •Drug B: Nitroglycerin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Nitroglycerin is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Sublingual nitroglycerin is indicated for the acute relief of an attack or acute prophylaxis of angina pectoris due to coronary artery disease. Transdermal nitroglycerin is indicated for the prevention of angina pectoris due to coronary artery disease. Intravenous nitroglycerin is indicated for the treatment of peri-operative hypertension; for control of congestive heart failure in the setting of acute myocardial infarction; for treatment of angina pectoris in patients who have not responded to sublingual nitroglycerin and beta (β)-blockers; and for induction of intraoperative hypotension. Topical nitroglycerin ointment is used to treat moderate to severe pain associated with chronic anal fissure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Nitroglycerin causes the relaxation of vascular smooth muscles, causing arteriolar and venous dilatation. It increases blood flow to the myocardium and reduces cardiac preload and afterload, decreasing myocardial wall stress and ameliorating anginal symptoms. Nitroglycerin also reduces coronary artery spasm, decreasing systemic vascular resistance as well as systolic and diastolic blood pressure. Like other organic nitrates, repeated and prolonged administration of nitroglycerin can lead to the development of tolerance or desensitization of vascular smooth muscle to further nitroglycerin-induced vasorelaxation. This loss of efficacy may be associated with the inhibition of mitochondrial aldehyde dehydrogenase, which is an important enzyme involved in the bioactivation of nitroglycerin. Nitroglycerin tolerance may be accompanied by pro-oxidant effects, endothelial dysfunction, and increased sensitivity to vasoconstrictors. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Nitroglycerin is converted by mitochondrial aldehyde dehydrogenase in smooth muscle cells to nitric oxide (NO), a potent vasodilator. NO activates the enzyme guanylate cyclase, which converts guanosine triphosphate (GTP) to cyclic guanosine 3',5'-monophosphate (cGMP) in vascular smooth muscle and other tissues. cGMP is an endogenous vasodilator of vascular smooth muscle: it causes protein kinase-dependent phosphorylation and activates downstream cascades that promote relaxation and increased blood flow in veins, arteries and cardiac tissue. An in vitro study using mouse aorta suggests that nitric oxide, an active metabolite of nitroglycerin, targets the natriuretic peptide receptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Nitroglycerin is rapidly absorbed and is often used in emergency situations for this reason. After a sublingual dose of 0.5 mg of nitroglycerin in patients with ischemic heart disease, the peak concentration (C max ) was 2.56 ng/mL and the mean T max was 4.4 minutes. The C max following a 0.6mg dose of sublingual nitroglycerin was 2.1 ng/mL and the T max was 7.2 minutes. The absolute bioavailability following sublingual administration was about 40%. The bioavailability of nitroglycerin depends on several factors, such as mucosal metabolism and hydration status, which both affect the absorption of sublingual drugs. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of nitroglycerin is 3 L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): After a sublingual dose of nitroglycerin, at concentrations in the plasma ranging from 50 to 500 ng/mL, plasma protein binding of nitroglycerin is about 60%. The plasma protein binding of the metabolites 1,2-dinitroglycerin is 60% and that of 1,3-dinitroglycerin is 30%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Mitochondrial aldehyde dehydrogenase 2 (ALDH2) promotes the bioactivation of nitroglycerin. Nitroglycerin is metabolized to nitrite; 1,2-glyceryl dinitrate; and 1,3 glyceryl dinitrate. Nitrite is further metabolized to nitric oxide. 1,2- and 1,3-dinitroglycerols are less biologically active than nitroglycerin but they have longer half-lives, which explains some prolonged effects of nitrates. Both dinitrates are finally metabolized to glycerol, carbon dioxide, and mononitrates that do not have vasodilatory actions. Nitroglycerin can also chemically react with a thiol to generate an intermediate S-nitrosothiol, which resulted in further production of nitric oxide. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Metabolism is the main route by which nitroglycerin is eliminated from the body. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Following intravenous administration, the plasma half-life is about three minutes. The estimated plasma half-life following sublingual administration is approximately six minutes. The elimination half-lives of metabolites 1,2-dinitroglycerin and 1,3-dinitroglycerin range between 32 to 26 minutes. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The estimated clearance following intravenous administration is 1 L/kg/min. The apparent clearance after a sublingual dose was 21.9 L/min in a pharmacokinetic study of patients with ischemic heart disease and angina. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD50 of nitroglycerin in rats is 105 mg/kg and the LD50 of the intravenous form in rats is 23.2 mg/kg. Nitrate overdosage can result in following conditions: severe hypotension, persistent throbbing headache, vertigo, palpitation, visual disturbance, flushing and perspiring skin (later becoming cold and cyanotic), nausea and vomiting (possibly with colic and even bloody diarrhea), syncope (especially in the upright posture), methemoglobinemia with cyanosis and anorexia, initial hyperpnea, dyspnea and slow breathing, slow pulse (dicrotic and intermittent), heart block, increased intracranial pressure with cerebral symptoms of confusion and moderate fever, paralysis and coma followed by clonic convulsions, and possibly death due to circulatory collapse. Methemoglobinemia can rarely occur at conventional doses of organic nitrates. This condition is dose-related and it can be even more pronounced in patients with genetic abnormalities of hemoglobin that favor methemoglobin formation. Methemoglobinemia can be managed with the administration of methylene blue unless the patient has a known G-6-PD deficiency. There are no known antidotes to an overdose of nitroglycerin, and it is not known whether its metabolites can be removed from the circulation. Hypotension associated with nitroglycerin overdose can be managed with different symptomatic and supportive measures, including the elevation of the lower limbs, administration of intravenous saline or other fluids to maintain central fluid volume, and administration of oxygen and artificial ventilation. Gastric lavage may be used in case of ingestion of excess nitroglycerin. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Gonitro, Minitran, Mylan-nitro, Nitro-bid, Nitro-dur, Nitroject, Nitrolingual, Nitromist, Nitrostat, Rectiv, Trinipatch •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1,2,3-propanetrioltrinitrate 1,2,3-propanetriyl nitrate Glycerin trinitrate (common) Glycerol trinitrate (common) Glycerol, nitric acid triester Glyceroli trinitratis (common) Glyceroltrinitrat (common) Glyceryl trinitrate (common) NG Nitroglicerina (common) Nitroglycerin (common) Nitroglycerine (common) Nitroglycerol (common) Nitromed (common) Propane-1,2,3-triyl trinitrate Trinitrine (common) Trinitroglycerin (common) Trinitroglycerol (common)

Do Abaloparatide and Nitroprusside interact?

•Drug A: Abaloparatide •Drug B: Nitroprusside •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Nitroprusside is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For immediate reduction of blood pressure of patients in hypertensive crises, reduce bleeding during surgery, and for the treatment of acute congestive heart failure •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Nitroprusside a powerful vasodilator relaxes the vascular smooth muscle and produce consequent dilatation of peripheral arteries and veins. Other smooth muscle (e.g., uterus, duodenum) is not affected. Sodium nitroprusside is more active on veins than on arteries. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): One molecule of sodium nitroprusside is metabolized by combination with hemoglobin to produce one molecule of cyanmethemoglobin and four CN- ions; methemoglobin, obtained from hemoglobin, can sequester cyanide as cyanmethemoglobin; thiosulfate reacts with cyanide to produce thiocyanate; thiocyanate is eliminated in the urine; cyanide not otherwise removed binds to cytochromes. Cyanide ion is normally found in serum; it is derived from dietary substrates and from tobacco smoke. Cyanide binds avidly (but reversibly) to ferric ion (Fe+++), most body stores of which are found in erythrocyte methemoglobin (metHgb) and in mitochondrial cytochromes. When CN is infused or generated within the bloodstream, essentially all of it is bound to methemoglobin until intraerythrocytic methemoglobin has been saturated. Sodium nitroprusside is further broken down in the circulation to release nitric oxide (NO), which activates guanylate cyclase in the vascular smooth muscle. This leads to increased production of intracellular cGMP, which stimulates calcium ion movement from the cytoplasm to the endoplasmic reticulum, reducing the level of available calcium ions that can bind to calmodulin. This ultimately results in vascular smooth muscle relaxation and vessel dilation. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Metabolized by reaction with hemoglobin to produce cyanmethemoglobin and cynide ions •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): One molecule of sodium nitroprusside is metabolized by combination with hemoglobin to produce one molecule of cyanmethemoglobin and four CN¯ ions, thiosulfate reacts with cyanide to produce thiocyanate, thiocyanate is eliminated in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Approximately 2 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdosage of nitroprusside can be manifested as excessive hypotension or cyanide toxicity or as thiocyanate toxicity. The acute intravenous mean lethal doses (LD 50 ) of nitroprusside in rabbits, dogs, mice, and rats are 2.8, 5.0, 8.4, and 11.2 mg/kg, respectively. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Nipride, Nipride RTU, Nitropress •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Nitrous acid interact?

•Drug A: Abaloparatide •Drug B: Nitrous acid •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Nitrous acid. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For sequential use with sodium thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Sodium nitrite reverses cyanide toxicity and produces blood vessel dilation. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Cyanide has a high affinity for the oxidized form of iron (Fe3+) such as that found in cytochrome oxidase a3. Cyanide binds to and inhibits cytochrome oxidase a3, preventing oxidative phophorylation from occuring. The resultant lack of ATP cannot support normal cellular processes, particularly in the brain. Compensatory increases in anaerobic respiration result in rising levels of lactic acid and subsequent acidosis. Nitrite primarily acts by oxidizing hemoglobin to methemoglobin. The now oxidized Fe3+ in methemoglobin also binds cyanide with high affinity and accepts cyanide from cytochrome a3. This leaves cytochrome a3 free to resume its function in oxidative phosphorylation. The slow dissociation of cyanide from methemoglobin allows hepatic enzymes such as rhodanese to detoxify the compound without further systemic toxicity occuring. Methemoglobin is reduced back to hemoglobin by methemoglobin reductase allowing the affected blood cells to resume normal functioning. The reduction of nitrite by hemoglobin results in the formation of nitric oxide. Nitric oxide acts as a powerful vasodilator, producing vascular smooth muscle relaxation through activation of soluble guanylate cyclase and the subsequent cyclic guanylyl triphosphate mediated signalling cascade. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Reduced by deoxyhemoglobin to form nitric oxide. Nitrite is also reduced to nitric oxide and further reduced to ammonia by gut bacteria. Nitrite can be oxidized to nitrate by oxyhemoglobin. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Half life of 0.4-0.78h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral LD50 of 157.9mg/kg observed in rats and 175mg/kg observed in mice. Estimated oral LD50 of 35mg/kg in humans. Sodium nitrite toxicity manifests as cardiovascular collapse following severe hypotension due to nitrite's vasodilatory action. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Nithiodote •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Obinutuzumab interact?

•Drug A: Abaloparatide •Drug B: Obinutuzumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Obinutuzumab. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Obinutuzumab is used as a combination treatment with chlorambucil to treat patients with untreated chronic lymphocytic leukemia. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Obinutuzumab is more potent than rituximab in depleting B-cells, antitumor activity, and tumor regression. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): In contrast to rituximab, which is a classic type I CD20 antibody, obinutuzumab binds to type II CD20 antibodies. This allows obinutuzumab to have a much higher induction of antibody-dependant cytotoxicity and a higher direct cytotoxic effect than the classic CD20 antibodies. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Obinutuzumab is administered intravenously, so its absorption is 100%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Obinutuzumab has a volume of distribution of about 3.8 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Obinutuzumab does not bind to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Obinutuzumab is not metabolized by the liver. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The route of elimination of obinutuzumab was not indicated (FDA label). •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half life of obinutuzumab is 28.4 days. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of obinutuzumab is 0.09L/day. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The most serious toxicities observed with obinutuzumab are Hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML). HBV reactivation can occur with all anti-CD20 antibodies and can result in hepatic failure, fulminant hepatitis, and death. PML occurs as a result of JC virus infection and can be fatal as well. Other common but less serious adverse reactions include infusion reactions (pre-treat with glucocorticoids, acetaminophen, and anti-histamine to prevent this), neutropenia, thrombocytopenia, and Tumor Lysis Syndrome (TLS) (pre-treat patients, especially with a high lymphocyte count and/or a high tumor burden, with anti-hyperuricemics and hydration). It is also recommended to NOT administer live virus vaccinations prior to or during obinutuzumab treatment. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Gazyva •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Olanzapine interact?

•Drug A: Abaloparatide •Drug B: Olanzapine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Olanzapine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Olanzapine was initially used orally and intramuscularly for the chronic treatment of schizophrenia in patients over 13 years old and other psychiatric disorders such as bipolar I disorder including mixed or manic episodes. Olanzapine is also indicated, in combination with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder in adults. As well, olanzapine is indicated, in combination with fluoxetine for the treatment of episodes of depression associated with bipolar disorder type 1 and treatment-resistant depression in patients over 10 years old. Olanzapine is also approved for the management of psychomotor agitation associated with schizophrenia and bipolar I mania. Schizophrenia is a complex biochemical brain disorder that affects the person's ability to differentiate reality. It is usually observed as the presence of delusions, hallucinations, social withdrawal and disturbed thinking. Bipolar disorder is a mental health condition defined by periods of extreme mood disturbances. It is categorized in different types from which type 1 is known to involve episodes of severe mania and often depression while type 2 presents less severe forms of mania. Olanzapine is also indicated in combination with samidorphan for the treatment of bipolar I disorder, either as an adjunct to lithium or valproate or as monotherapy for the acute treatment of manic or mixed episodes or as maintenance therapy, and for the treatment of schizophrenia in adults. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): The effect of olanzapine in the D2 receptor is reported to produce the positive effects of this drug such as a decrease in hallucinations, delusions, disorganized speech, disorganized thought, and disorganized behavior. On the other hand, its effect on the serotonin 5HT2A receptor prevents the onset of anhedonia, flat affect, alogia, avolition and poor attention. Based on the specific mechanism of action, olanzapine presents a higher affinity for the dopamine D2 receptor when compared to the rest of the dopamine receptor isotypes. This characteristic significantly reduces the presence of side effects. Clinical trials for the original use of olanzapine demonstrated significant effectiveness in the treatment of schizophrenia and bipolar disorder in adults and acute manic or mixed episodes associated with bipolar disorder in adolescents. The effect of olanzapine on dopamine and serotonin receptors has been suggested to reduce chemotherapy-induced nausea and vomiting as those receptors are suggested to be involved in this process. For this effect, several clinical trials have been conducted and it has been shown that olanzapine can produce a significant increase in total control of nausea and vomiting. In a high-level study of the effect of olanzapine for this condition, a complete response on the delay phase was observed in 84% of the individual and control of emesis of over 80% despite the phase. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The activity of olanzapine is achieved by the antagonism of multiple neuronal receptors including the dopamine receptor D1, D2, D3 and D4 in the brain, the serotonin receptors 5HT2A, 5HT2C, 5HT3 and 5HT6, the alpha-1 adrenergic receptor, the histamine receptor H1 and multiple muscarinic receptors. As abovementioned, olanzapine presents a wide profile of targets, however, its antagonistic effect towards the dopamine D2 receptor in the mesolimbic pathway is key as it blocks dopamine from having a potential action at the post-synaptic receptor. The binding of olanzapine to the dopamine D2 receptors is easily dissociable and hence, it allows for a certain degree of dopamine neurotransmission. On the other hand, olanzapine acts in the serotonin 5HT2A receptors in the frontal cortex in a similar manner than the reported on dopamine D2 receptors. This determined effect allows for a decrease in adverse effects. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Olanzapine presents a linear pharmacokinetic profile and, after daily administration, it reaches steady-state in about a week. Under the administration of a normal dosage of olanzapine, the steady-state plasma concentration does not seem to exceed 150 ng/ml with an AUC of 333 ng/h/ml. The absorption of olanzapine is not affected by the concomitant administration of food. The pharmacokinetic profile of olanzapine is characterized by reaching peak plasma concentration of 156.9 ng/ml approximately 6 hours after oral administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of olanzapine is reported to be of 1000 liters which indicate a large distribution throughout the body. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Olanzapine is largely bound to plasma proteins and hence, about 93% of the administered dose is bound. The main proteins for binding are albumin and alpha-1 acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Olanzapine is greatly metabolized in the liver, which represents around 40% of the administered dose, mainly by the activity of glucuronide enzymes and by the cytochrome P450 system. From the CYP system, the main metabolic enzymes are CYP1A2 and CYP2D6. As part of the phase I metabolism, the major circulating metabolites of olanzapine, accounting for approximate 50-60% of this phase, are the 10-N-glucuronide and the 4'-N-desmethyl olanzapine which are clinically inactive and formed by the activity of CYP1A2. On the other hand, CYP2D6 catalyzes the formation of 2-OH olanzapine and the flavin-containing monooxygenase (FMO3) is responsible for N-oxide olanzapine. On the phase II metabolism of olanzapine, UGT1A4 is the key player by generating direct conjugation forms of olanzapine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Olanzapine is mainly eliminated through metabolism and hence, only 7% of the eliminated drug can be found as the unchanged form. It is mainly excreted in the urine which represents around 53% of the excreted dose followed by the feces that represent about 30%. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Olanzapine presents a half-life ranging between 21 to 54 hours with an average half-life of 30 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The mean clearance rate of olanzapine is of 29.4 L/hour however, some studies have reported an apparent clearance of 25 L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The toxicity symptoms of olanzapine are known to include somnolence, mydriasis, blurred vision, respiratory depression, hypotension, extrapyramidal symptoms and anticholinergic effects. The overdosage effects in children are generally associated with more significant side effects. The maximum registered dosage of olanzapine in clinical trials was of 300 mg and it was reported to present drowsiness and slurred speech. However, on post-marketing surveillance, a wide range of symptoms have been presented including agitation, dysarthria, tachycardia, extrapyramidal symptoms, and reduced consciousness. One case of overdosage-driven death was reported after ingestion of 450 mg of olanzapine. In the cases of acute overdosage, the establishment of adequate oxygenation and ventilation, gastric lavage and administration of activated charcoal with a laxative is recommended. In carcinogenesis studies, olanzapine was showed to present an increase in the incidence of liver hemangiomas and hemangiosarcomas as well as mammary gland adenomas, and adenocarcinomas. On fertility studies, there was solely found impairment in male mating performance and delays in ovulation. There is no evidence of mutagenic, genotoxic potential not adverse events on fertility. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Lybalvi, Olazax, Symbyax, Zalasta, Zypadhera, Zyprexa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine Olanzapin (common) Olanzapina (common) Olanzapine (common) Olanzapinum (common)

Do Abaloparatide and Olmesartan interact?

•Drug A: Abaloparatide •Drug B: Olmesartan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Olmesartan is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Olmesartan is indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents. Olmesartan is also used off-label for the management Type 2 Diabetes-associated nephropathy, heart failure, and post-myocardial infarction, particularly in patients who are unable to tolerate ACE inhibitors. ARBs such as olmesartan have been shown in a number of large-scale clinical outcomes trials to improve cardiovascular outcomes including reducing risk of myocardial infarction, stroke, the progression of heart failure, and hospitalization. Like other ARBs, olmesartan blockade of RAAS slows the progression of diabetic nephropathy due to its renoprotective effects. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Overall, olmesartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium. Hypotension in Volume- or Salt-Depleted Patients In patients with an activated renin-angiotensin aldosterone system, such as volume-and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be anticipated after initiation of treatment with olmesartan. Initiate treatment under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Valvular Stenosis: there is concern on theoretical grounds that patients with aortic stenosis might be at a particular risk of decreased coronary perfusion, because they do not develop as much afterload reduction. Impaired Renal Function As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with olmesartan. In patients whose renal function may depend upon the activity of the renin-angiotensin- aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. Similar results may be anticipated in patients treated with olmesartan. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected. Sprue-like Enteropathy Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of olmesartan medoxomil in cases where no other etiology is identified. Electrolyte Imbalances Olmesartan medoxomil contains olmesartan, a drug that inhibits the renin-angiotensin system (RAS). Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Olmesartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which also includes telmisartan, candesartan, losartan, valsartan, and irbesartan. ARBs selectively bind to angiotensin receptor 1 (AT1) and prevent the protein angiotensin II from binding and exerting its hypertensive effects. As the principal pressor agent of the renin-angiotensin system, Angiotensin II causes vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis. Overall, olmesartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium. Olmesartan also effects on the renin-angiotensin aldosterone system (RAAS) plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS, which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and preventing ventricular hypertrophy and remodelling. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): When taken orally, the prodrug olmesartan medoxomil is rapidly absorbed in the gastrointestinal tract and metabolized to olmesartan. The esterification with medoxomil was created with the intention of increasing olmesartan bioavailability from 4.5% to 28.6%. Oral administration of 10-160 mg of olmesartan has been shown to reach peak plasma concentration of 0.22-2.1 mg/L after 1-3 hours with an AUC of 1.6-19.9mgh/L. The pharmacokinetic profile of olmesartan has been observed to be nearly linear and dose-dependent under the therapeutic range. The steady-state level of olmesartan is achieved after once a day dosing during 3 to 5 days. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 17 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Olmesartan is highly bound to plasma proteins. 99% of the administered dose is found in a bound state with no penetration in red blood cells. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. This rapid first-pass metabolism was confirmed by the lack of measurable amounts of olmesartan medoxomil in plasma or excreta. This first-pass metabolism is not driven by cytochrome enzymes and hence it is not expected to interact with other drugs via this mechanism. The pharmacologically active moiety does not appear to undergo further metabolism. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The main elimination route of olmesartan is in the unchanged form through the feces. From the systemically bioavailable dose, about 10-16% is eliminated in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean plasma olmesartan half-life is reported to be from 10-15 hours after multiple oral administration. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total plasma clearance is 1.3 L/h and the renal clearance is 0.6 L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The reported LD50 of olmesartan in dogs was reported to be greater of 1500 mg/kg. Overdose is expressed as hypotension, tachycardia, and bradycardia when there is parasympathetic stimulation. In case of overdose, supportive treatment is recommended. Olmesartan was shown to be safe on carcinogenic and fertility studies. However, in in vitro mutagenic studies showed a potential to induce chromosomal aberrations in cells and it tested positive for thymidine kinase mutations in the mouse lymphoma assay. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Azor, Benicar, Benicar Hct, Olmetec, Olmetec Plus, Tribenzor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid 4-(hydroxy-1-methylethyl)-2-propyl-1-{[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid Olmesartan (common)

Do Abaloparatide and Opicapone interact?

•Drug A: Abaloparatide •Drug B: Opicapone •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Opicapone. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Opicapone is indicated as adjunctive therapy in adults with Parkinson’s disease and end-of-dose motor fluctuations or “off” episodes whose symptoms cannot be stabilized on the combination therapy of levodopa and DOPA decarboxylase inhibitor (e.g., carbidopa). •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Opicapone is a COMT inhibitor that serves to improve the availability and duration of action of levodopa (L-Dopa), a standard pharmacological treatment for Parkinson's Disease. Opicapone works by blocking the peripheral degradation of L-Dopa mediated by COMT. Opicapone has a long duration of action: following administration of a 50 mg dose, COMT inhibition lasted for more than 24 hours. In clinical trials, opicapone as adjunct therapy to L-Dopa plus a dopa decarboxylase inhibitor significantly improved motor fluctuations than placebo, and the effects were comparable to entacapone. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Levodopa (L-Dopa) is the gold standard for managing motor and some non-motor symptoms associated with Parkinson's Disease; however, only a small fraction of administered L-Dopa actually crosses the blood-brain barrier to exert its therapeutic action and patients face the risk of developing end-of-dose motor fluctuations, which reflects the rapid peripheral metabolism of L-dopa by aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT). Opicapone is a peripheral, selective, and reversible catechol-O-methyltransferase (COMT) inhibitor. It displays a high binding affinity that is in sub-picomolar ranges, resulting in a slow complex dissociation rate constant and long duration of action in vivo. When opicapone is added to the treatment regimen that contains L-Dopa and DOPA decarboxylase inhibitor, opicapone helps to increase the plasma levels and enhance the therapeutic efficacy of L-Dopa. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Orally administered opicapone demonstrates a linear, dose-dependent absorption profile. Opicapone is rapidly absorbed, with an oral bioavailability of about 20%. Following administration of a single 50 mg dose of opicapone, the median T max was two hours, ranging from one to four hours. A moderate fat or moderate calorie meal was shown to decrease the C max by 62%, the mean overall plasma exposure (AUC) by 31%, and the Tmax by 4 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Following oral administration, the apparent V d of opicapone at a dose of 50 mg was 29 L with an inter-subject variability of 36%. One study showed small systemic accumulation after multiple-dosing. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Opicapone is >99% bound to plasma proteins, which is independent of the drug concentration. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): According to clinical and in vitro studies, sulphation is the primary metabolic pathway of opicapone, forming the inactive metabolite. Opicapone can also undergo glucuronidation, COMT-mediated methylation, reduction, and glutathione conjugation. As two major circulating metabolites, BIA 9-1103 (3-O-sulphated opicapone) accounts for 67.1% of the total radioactivity and BIA 9-1104 (4-O-methylated opicapone) accounts for 20.5% of the total radioactivity. Other metabolites are generally unquantifiable in plasma samples. Opicapone can undergo N-oxide reduction to form BIA 9-1079, which was shown to be an active metabolite in non-clinical studies; however, it is generally undetectable in humans. Other inactive metabolites include BIA 9-1100, BIA 9-1101, and BIA 9-1106. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following administration of a single 100 mg dose of radiolabeled opicapone in healthy subjects, about 70% of the total dose was recovered in feces, where 22% of the recovered dose was excreted as an unchanged parent drug. About 20% of the total dose was recovered in exhaled air and about 5% was recovered in the urine, where less than 1% of the recovered dose was in an unchanged form. The primary detectable metabolite in the urine was the glucuronide metabolite. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean elimination half-life of opicapone is one to two hours. Despite the short half-life, the observed half-life of opicapone-induced COMT inhibition in human red blood cells was 61.6 hours with a standard deviation of 37.6 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Following oral administration of 50 mg opicapone, the apparent total body clearance was 22 L/h, with an inter-subject variability of 45%. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): There is no reported LD 50 data of opicapone. As there is no known antidote for opicapone overdose, overdosage should be managed with symptomatic and supportive treatment. Removal of the drug through gastric lavage and/or inactivation by administering activated charcoal should be considered. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Ongentys •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Paclitaxel interact?

•Drug A: Abaloparatide •Drug B: Paclitaxel •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Paclitaxel is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used in the treatment of Kaposi's sarcoma and cancer of the lung, ovarian, and breast. Abraxane® is specfically indicated for the treatment of metastatic breast cancer and locally advanced or metastatic non-small cell lung cancer. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Paclitaxel is a taxoid antineoplastic agent indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary, and other various cancers including breast cancer. Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Paclitaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, paclitaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner. Specifically, paclitaxel binds to the β subunit of tubulin. Tubulin is the "building block" of mictotubules, and the binding of paclitaxel locks these building blocks in place. The resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the maximum plasma concentration (Cmax) is 195 ng/mL, while the AUC is 6300 ng•h/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 227 to 688 L/m^2 [apparent volume of distribution at steady-state, 24 hour infusion] •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 89%-98% bound to plasma protein. The presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6a-hydrox-ypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6a, 3’-p-dihydroxypaclitaxel, by CYP3A4. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): In 5 patients administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the elimination half=life is 52.7 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 21.7 L/h/m2 [Dose 135 mg/m2, infusion duration 24 h] 23.8 L/h/m2 [Dose 175 mg/m2, infusion duration 24 h] 7 L/h/m2 [Dose 135 mg/m2, infusion duration 3 h] 12.2 L/h/m2 [Dose 175 mg/m2, infusion duration 3 h] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Rat (ipr) LD 50 =32530 µg/kg. Symptoms of overdose include bone marrow suppression, peripheral neurotoxicity, and mucositis. Overdoses in pediatric patients may be associated with acute ethanol toxicity. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Abraxane, Taxol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5beta,20-Epoxy-1,2-alpha,4,7beta,10beta,13alpha-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine ABI-007 COMPONENT PACLITAXEL (common) BENZENEPROPANOIC ACID, .BETA.-(BENZOYLAMINO)-.ALPHA.-HYDROXY-, (2AR,4S,4AS,6R,9S,11S,12S,12AR,12BS)-6,12B-BIS(ACETYLOXY)-12-(BENZOYLOXY)-2A,3,4,4A,5,6,9,10,11,12,12A,12B-DODECAHYDRO-4,11-DIHYDROXY-4A,8,13,13-TETRAMETHYL-5-OXO-7,11-METHANO-1H-CYCLODECA(3, (common) liposomal encapsulated paclitaxel (common) NAB-PACLITAXEL COMPONENT PACLITAXEL (common) Nanoparticulate paclitaxel (common) Paclitaxel (common) paclitaxel protein-bound particles (common) Paclitaxel protein-bound particles for injection suspension (common) Taxol A (common)

Do Abaloparatide and Papaverine interact?

•Drug A: Abaloparatide •Drug B: Papaverine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Papaverine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of impotence and vasospasms. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Papaverine is a nonxanthine phosphodiesterase inhibitor for the relief of cerebral and peripheral ischemia associated with arterial spasm and myocardial ischemia complicated by arrhythmias. The main actions of Papaverine are exerted on cardiac and smooth muscle. Like qathidine, Papaverine acts directly on the heart muscle to depress conduction and prolong the refractory period. Papaverine relaxes various smooth muscles. This relaxation may be prominent if spasm exists. The muscle cell is not paralyzed by Papaverine and still responds to drugs and other stimuli causing contraction. The antispasmodic effect is a direct one, and unrelated to muscle innervation. Papaverine is practically devoid of effects on the central nervous system. Papaverine relaxes the smooth musculature of the larger blood vessels, especially coronary, systemic peripheral, and pulmonary arteries. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Perhaps by its direct vasodilating action on cerebral blood vessels, Papaverine increases cerebral blood flow and decreases cerebral vascular resistance in normal subjects; oxygen consumption is unaltered. These effects may explain the benefit reported from the drug in cerebral vascular encephalopathy. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): ~90% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 0.5-2 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Penbutolol interact?

•Drug A: Abaloparatide •Drug B: Penbutolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Penbutolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Penbutolol is indicated in the treatment of mild to moderate arterial hypertension. It may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.Penbutolol is contraindicated in patients with cardiogenic shock, sinus bradycardia, second and third degree atrioventricular conduction block, bronchial asthma, and those with known hypersensitivity. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Penbutolol is a ß-1, ß-2 (nonselective) adrenergic receptor antagonist. Experimental studies showed a dose-dependent increase in heart rate in reserpinized (norepinephrine-depleted) rats given penbutolol intravenously at doses of 0.25 to 1.0 mg/kg, suggesting that penbutolol has some intrinsic sympathomimetic activity. In human studies, however, heart rate decreases have been similar to those seen with propranolol. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Penbutolol acts on the β1 adrenergic receptors in both the heart and the kidney. When β1 receptors are activated by catecholamines, they stimulate a coupled G protein that leads to the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). The increase in cAMP leads to activation of protein kinase A (PKA), which alters the movement of calcium ions in heart muscle and increases the heart rate. Penbutolol blocks the catecholamine activation of β1 adrenergic receptors and decreases heart rate, which lowers blood pressure. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): >90%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 80-98% bound to plasma proteins. Extensively bound to Alpha-1-acid glycoprotein 1. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Metabolized in the liver by hydroxylation and glucuroconjugation forming a glucuronide metabolite and a semi-active 4-hydroxy metabolite. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The metabolites are excreted principally in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Plasma= approximately 5h Conjugated= approximately 20h in healthy persons, 25h in healthy elderly persons, and 100h in patients on renal dialysis. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Approximately 90% of the metabolites are excreted in the urine. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include drowsiness, vertigo, headache, and atriventricular block. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (2S)-1-(tert-butylamino)-3-(2-cyclopentylphenoxy)propan-2-ol Penbutolol (common) Penbutololum (common)

Do Abaloparatide and Pentobarbital interact?

•Drug A: Abaloparatide •Drug B: Pentobarbital •Severity: MODERATE •Description: Pentobarbital may increase the hypotensive activities of Abaloparatide. •Extended Description: The use of barbiturates may increase hypotension.1,2 Therefore, the concomitant administration of barbiturates and hypotensive agents may lead to dangerous hypotension due to additive effects. •References: 1. Suddock JT, Cain MD: Barbiturate Toxicity . [https://go.drugbank.com/articles/A233155] 2. Roberts I, Sydenham E: Barbiturates for acute traumatic brain injury. Cochrane Database Syst Rev. 2012 Dec 12;12(12):CD000033. doi: 10.1002/14651858.CD000033.pub2. [https://go.drugbank.com/articles/A259951] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the short-term treatment of insomnia. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Pentobarbital, a barbiturate, is used for the treatment of short term insomnia. It belongs to a group of medicines called central nervous system (CNS) depressants that induce drowsiness and relieve tension or nervousness. Little analgesia is conferred by barbiturates; their use in the presence of pain may result in excitation. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Pentobarbital binds at a distinct binding site associated with a Cl- ionopore at the GABAA receptor, increasing the duration of time for which the Cl- ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged. All of these effects are associated with marked decreases in GABA-sensitive neuronal calcium conductance (gCa). The net result of barbiturate action is acute potentiation of inhibitory GABAergic tone. Barbiturates also act through potent (if less well characterized) and direct inhibition of excitatory AMPA-type glutamate receptors, resulting in a profound suppression of glutamatergic neurotransmission. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Barbiturates are absorbed in varying degrees following oral, rectal, or parenteral administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): by hepatic microsomal enzyme system •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Barbiturates are metabolized primarily by the hepatic microsomal enzyme system, and the metabolic products are excreted in the urine, and less commonly, in the feces. Approximately 25 to 50 percent of a dose of aprobarbital or phenobarbital is eliminated unchanged in the urine, whereas the amount of other barbiturates excreted unchanged in the urine is negligible. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 5 to 50 hours (dose dependent) •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of an overdose typically include sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgment, drowsiness or coma, shallow breathing, staggering, and in severe cases coma and death. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Nembutal •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5-Ethyl-5-(1-methyl-butyl)-pyrimidine-2,4,6-trione 5-Ethyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione 5-ethyl-5-(1-methylbutyl)barbituric acid 5-ethyl-5-(sec-pentyl)barbituric acid Pentobarbital (common) Pentobarbitone (common)

Do Abaloparatide and Perindopril interact?

•Drug A: Abaloparatide •Drug B: Perindopril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Perindopril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of mild to moderate essential hypertension, mild to moderate congestive heart failure, and to reduce the cardiovascular risk of individuals with hypertension or post-myocardial infarction and stable coronary disease. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Perindopril is a nonsulfhydryl prodrug that is metabolized via first pass effect (62%) and systemic hydrolysis (38%) to perindoprilat, its active metabolite, following oral administration. Perindoprilat lowers blood pressure by antagonizing the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain the effects of perindoprilat by causing increased vasodilation and decreased blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Perindoprilat, the active metabolite of perindopril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Perindopril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapidly absorbed with peak plasma concentrations occurring approximately 1 hour after oral administration. Bioavailability is 65-75%. Following absorption, perindopril is hydrolyzed to perindoprilat, which has an average bioavailability of 20%. The rate and extent of absorption is unaffected by food. However, food decreases the extent of biotransformation to peridoprilat and reduces its bioavailability by 35%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Perindoprilat, 10-20% bound to plasma proteins •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Extensively metabolized, with only 4-12% of the dose recovered in urine following oral administration. Six metabolites have been identified: perindoprilat, perindopril glucuronide, perindoprilat glucuronide, a perindopril lactam, and two perindoprilat lactams. Only perindoprilat is pharmacologically active. Peridoprilat and perindoprilat glucuronide are the two main circulating metabolites. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Perindopril, 1.2 hours; Peridoprilat, 30-120 hours. The long half life of peridoprilat is due to its slow dissociation from ACE binding sites. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 219 - 362 mL/min [oral administration] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The most likely symptom of overdose is severe hypotension. The most common adverse effects observed in controlled clinical trials include cough, digestive symptoms, fatigue, headache, and dizziness. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Aceon, Coversyl, Prestalia, Viacoram •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (2S,3aS,7aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxopentan-2-yl]amino}propanoyl]octahydro-1H-indole-2-carboxylic acid Perindopril (common) Perindoprilum (common)

Do Abaloparatide and Phenelzine interact?

•Drug A: Abaloparatide •Drug B: Phenelzine •Severity: MODERATE •Description: Phenelzine may increase the orthostatic hypotensive activities of Abaloparatide. •Extended Description: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. •References: 1. Cockhill LA, Remick RA: Blood pressure effects of monoamine oxidase inhibitors--the highs and lows. Can J Psychiatry. 1987 Dec;32(9):803-8. [https://go.drugbank.com/articles/A36302] 2. Remick RA, Froese C: Monoamine oxidase inhibitors: clinical review. Can Fam Physician. 1990 Jun;36:1151-5. [https://go.drugbank.com/articles/A36361] 3. Delini-Stula A, Baier D, Kohnen R, Laux G, Philipp M, Scholz HJ: Undesirable blood pressure changes under naturalistic treatment with moclobemide, a reversible MAO-A inhibitor--results of the drug utilization observation studies. Pharmacopsychiatry. 1999 Mar;32(2):61-7. doi: 10.1055/s-2007-979193. [https://go.drugbank.com/articles/A36609] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Phenelzine is indicated for the treatment of nonendogenous, neurotic or atypical depression for patients that do not tolerate other forms of therapy. Atypical depression has a high prevalence rate, starts in early life, tends to last longer, is more likely to occur in people with bipolar disorder, has a high comorbidity with anxiety disorder and carries more risk of suicidal behavior. It is important to specify the atypical feature to predict the clinical course of depression and hence generate the best treatment and service. The featuring symptoms of the atypical feature include mood reactivity, two or more of this symptoms: 1) increased appetite, 2) increased sleep, 3) leaden paralysis and 4) interpersonal rejection sensitivity and should not have melancholic or catatonic features of depression. Neurotic depression is a depression of an emotionally unstable person. It is a secondary condition to major personality disorder, neuroses and drug use disorders. Likewise, a primary depression with a family history of depression spectrum disease would fit in this category. A nonendogenous depression is characterized by a disturbance in mood and general outlook. The physical symptoms tend to be less severe and it often occurs in response to stressful life events that keep occurring over a large period of time generating a continuous stress in the daily living. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): The elimination of monoamine oxidase by phenelzine results in the elevation of brain amines such as 2-phenylethylamine which is a metabolite of phenelzine. These amines have then marked effects on the uptake and release of catecholamines and serotonin in nerve endings. Phenelzine is shown to elevate brain levels of the gamma-aminobutyric acid (GABA) and alanine (ALA) as well as to inhibit the activity of the transaminases that normally metabolize these amino acids. In preclinical studies, it has been shown to be neuroprotective in cerebral ischemia. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The basic mechanism of action of phenelzine acts as an inhibitor and substrate of monoamine oxidase which subsequently causes an elevation in brain levels of catecholamines and serotonin. It also presents a similar structure to amphetamine which explains the effect on the uptake and release of dopamine, noradrenaline, and serotonin. Phenelzine has been reported to inhibit tyrosine aminotransferase, aromatic amino acid decarboxylase, and dopamine B-hydroxylase. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Phenelzine is rapidly absorbed from the gastrointestinal tract. The decay of the drug action is not dependent on the pharmacokinetic parameters but on the rate of protein synthesis which restores the functional levels of monoamine oxidase. The mean Cmax is 19.8 ng/ml and it occurs after 43 minutes of dose administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of phenelzine is hard to determine as drugs from this kind penetrate the CNS very well into the tissue where their activity is desired. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Unchanged phenelzine presents a high protein binding which reduced its bioavailability. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): For the metabolic studies, it is assumed that phenelzine is acetylated. Some of the metabolites of phenelzine are phenylacetic acid, 2-phenylethylamine and 4-hydroxyphenylacetic acid as major metabolites and N-acetyl-phenelzine as a minor metabolite. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The elimination of the administered dose is mainly composed of the phenelzine metabolites, phenylacetic acid and parahydroxyphenylacetic acid that constitute 79% of the dose found in the urine in the first 96 hours. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): After administration phenelzine presents a very short half-life of 11.6 hours in humans. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Phenelzine, as must of the monoamine oxidase inhibitors, can cause transient, mild and asymptomatic aminotransferase elevations. It has also been reported to be associated with cases of liver injury after 1-3 months of treatment. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Nardil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Phenobarbital interact?

•Drug A: Abaloparatide •Drug B: Phenobarbital •Severity: MODERATE •Description: Phenobarbital may increase the hypotensive activities of Abaloparatide. •Extended Description: The use of barbiturates may increase hypotension.1,2 Therefore, the concomitant administration of barbiturates and hypotensive agents may lead to dangerous hypotension due to additive effects. •References: 1. Suddock JT, Cain MD: Barbiturate Toxicity . [https://go.drugbank.com/articles/A233155] 2. Roberts I, Sydenham E: Barbiturates for acute traumatic brain injury. Cochrane Database Syst Rev. 2012 Dec 12;12(12):CD000033. doi: 10.1002/14651858.CD000033.pub2. [https://go.drugbank.com/articles/A259951] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of all types of seizures except absence seizures. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Phenobarbital, the longest-acting barbiturate, is used for its anticonvulsant and sedative-hypnotic properties in the management of all seizure disorders except absence (petit mal). •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Phenobarbital acts on GABAA receptors, increasing synaptic inhibition. This has the effect of elevating seizure threshold and reducing the spread of seizure activity from a seizure focus. Phenobarbital may also inhibit calcium channels, resulting in a decrease in excitatory transmitter release. The sedative-hypnotic effects of phenobarbital are likely the result of its effect on the polysynaptic midbrain reticular formation, which controls CNS arousal. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Absorbed in varying degrees following oral, rectal or parenteral administration. The salts are more rapidly absorbed than are the acids. The rate of absorption is increased if the sodium salt is ingested as a dilute solution or taken on an empty stomach. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 20 to 45% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic (mostly via CYP2C19). •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 53 to 118 hours (mean 79 hours) •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): CNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning they may wshow paralytic dilation), oliguria, tachycardia, hypotension, lowered body temperature, and coma. Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Donnatal, Luminal, Phenobarb, Phenohytro, Sezaby •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5-ethyl-5-phenyl-2,4,6(1H,3H,5H)-pyrimidinetrione 5-Ethyl-5-phenyl-pyrimidine-2,4,6-trione 5-Ethyl-5-phenylbarbituric acid 5-ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione 5-Phenyl-5-ethylbarbituric acid Fenobarbital (common) Phenobarbital (common) Phenobarbitol (common) Phenobarbitone (common) Phenobarbituric Acid (common) Phenyläthylbarbitursäure (common) Phenylethylbarbiturate (common) Phenylethylbarbituric Acid (common) Phenylethylbarbitursäure (common) Phenylethylmalonylurea (common)

Do Abaloparatide and Phenoxybenzamine interact?

•Drug A: Abaloparatide •Drug B: Phenoxybenzamine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Phenoxybenzamine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of phaeochromocytoma (malignant), benign prostatic hypertrophy and malignant essential hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Phenoxybenzamine is indicated for the control of episodes of hypertension and sweating that occur with a disease called pheochromocytoma. If tachycardia is excessive, it may be necessary to use a beta-blocking agent concomitantly. Phenoxybenzamine is a long-acting, adrenergic, alpha-receptor blocking agent which can produce and maintain "chemical sympathectomy" by oral administration. It increases blood flow to the skin, mucosa and abdominal viscera, and lowers both supine and erect blood pressures. It has no effect on the parasympathetic system. Phenoxybenzamine works by blocking alpha receptors in certain parts of the body. Alpha receptors are present in the muscle that lines the walls of blood vessels. When the receptors are blocked by Phenoxybenzamine, the muscle relaxes and the blood vessels widen. This widening of the blood vessels results in a lowering of blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Phenoxybenzamine produces its therapeutic actions by blocking alpha receptors, leading to a muscle relaxation and a widening of the blood vessels. This widening of the blood vessels results in a lowering of blood pressure. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Twenty to 30 percent of orally administered phenoxybenzamine appears to be absorbed in the active form. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 24 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose are largely the result of block of the sympathetic nervous system and of the circulating epinephrine. They may include postural hypotension resulting in dizziness or fainting, tachycardia, particularly postural, vomiting; lethargy, and shock. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Dibenzyline •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fenossibenzamina (common) Fenoxibenzamina (common) Phenoxybenzamine (common) Phenoxybenzaminum (common) POB

Do Abaloparatide and Phentolamine interact?

•Drug A: Abaloparatide •Drug B: Phentolamine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Phentolamine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): When used intravenously or intramuscularly, phentolamine is used to prevent or control hypertensive episodes that may occur in a patient with pheochromocytoma due to stress or manipulation during preoperative preparation and surgical excision. It is also used to prevent or treat dermal necrosis and sloughing following intravenous administration or extravasation of norepinephrine. It may be used to diagnose pheochromocytoma by the phentolamine-blocking test. Submucosal injection of phentolamine is indicated for the reversal of soft-tissue anesthesia (e.g. anesthesia of the lip and tongue) and the associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor in patients three years old and older. Phentolamine ophthalmic solution is used to treat pharmacologically-induced mydriasis produced by adrenergic agonists (e.g., phenylephrine) or parasympatholytic (e.g., tropicamide) agents. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Phentolamine produces an alpha-adrenergic block of a relatively short duration. Phentolamine induces vasodilatation of vascular smooth muscle and pupils. When used in an ophthalmic solution, the onset of pupil dilation generally occurred in 30 minutes, with the maximal effect seen in 60 to 90 minutes. Pupil dilation lasted for at least 24 hours. Phentolamine also has direct but less marked positive inotropic and chronotropic effects on cardiac muscle and vasodilator effects on vascular smooth muscle; however, phentolamine is not believed to affect contractile or adenyl cyclase function. Large doses can lead to a mild sympatholytic action. Some evidence suggests that phentolamine also stimulates beta-adrenergic receptors, thereby causing peripheral vasodilation. Phentolamine was shown to stimulate insulin secretion, possibly related to its blocking actions on ATP-sensitive K channels. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Phentolamine is a reversible, competitive antagonist at alpha-1 and alpha-2 adrenergic receptors. It causes vasodilation of vascular smooth muscles. Pupil dilation is primarily controlled by the radial iris dilator muscles surrounding the pupil, which are activated by the alpha-1 adrenergic receptors. Phentolamine reversibly binds to these receptors and reduces pupil diameter. By blocking alpha-1 adrenergic receptors, phentolamine can also be used to reverse mydriasis induced by muscarinic antagonists. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The peak concentrations of phentolamine are achieved within 10 to 20 minutes following submucosal administration. The C max was higher in children with greater weights. Following topical ocular administration of phentolamine ophthalmic solution 0.75%, the peak concentration levels were achieved between 15 minutes and one hour after dosing with the median value of 0.45 ng/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): While there is limited information on phentolamine distribution, the drug is reported to cross the blood-brain barrier. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 13% of a single intravenous dose appears in the urine as unchanged drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Phentolamine has a half-life of 19 minutes following intravenous administration. The terminal elimination half-life of phentolamine was approximately two to three hours following submucosal administration. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 of phentolamine mesylate, a salt of phentolamine, was 1250 mg/kg in rats and 1000-1100 mg/kg in mice. No deaths due to acute poisoning with phentolamine have been reported. Overdosage with phentolamine is characterized chiefly by cardiovascular disturbances, such as arrhythmias, tachycardia, hypotension, and possibly shock. Other possible signs and symptoms include excitation, headache, sweating, pupillary contraction, visual disturbances, nausea, vomiting, diarrhea, and hypoglycemia. There is no specific antidote: Treatment consists of appropriate monitoring and supportive care. A plasma expander and norepinephrine may be administered to manage decreased blood pressure. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Oraverse •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-(N-(m-hydroxyphenyl)-p-toluidinomethyl)imidazoline 3-((4,5-DIHYDRO-1H-IMIDAZOL-2-YLMETHYL)(4-METHYLPHENYL)AMINO)PHENOL (common) Fentolamina (common) Phentolamin (common) Phentolamine (common) Phentolaminum (common)

Do Abaloparatide and Pindolol interact?

•Drug A: Abaloparatide •Drug B: Pindolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Pindolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Pindolol is indicated in the management of hypertension. In Canada, it is also indicated in the prophylaxis of angina. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Pindolol is a nonselective beta blocker indicated in the management of hypertension and prophylaxis of angina. It has a short duration of action as it is given twice daily, and a wide therapeutic window as doses can range from 10-60 mg/day. Patients should be counselled regarding the risk of cardiac failure, exacerbating ischemic heart disease with sudden withdrawal, nonallergic bronchospasm, masking hypoglycemia in diabetics, and masking hyperthyroidism. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The beta-1 adrenoceptor is a G-protein-coupled receptor. Agonism of the beta-1 adrenoceptor allows the Gs subunit to upregulate adenylyl cyclase, converting ATP to cyclic AMP (cAMP). Increased concentrations of cAMP activate cAMP-dependant kinase A, phosphorylating calcium channels, raising intracellular calcium, increasing calcium exchange through the sarcoplasmic reticulum, and increasing cardiac inotropy. cAMP-dependant kinase A also phosphorylates myosin light chains, increasing smooth muscle contractility. Increased smooth muscle contractility in the kidney releases renin. Pindolol is a non-selective beta blocker. Blocking beta-1 adrenergic receptors in the heart results in decreased heart rate and blood pressure. By blocking beta-1 receptors in the juxtaglomerular apparatus, pindolol inhibits the release of renin, which inhibits angiotensin II and aldosterone release. Reduced angiotensin II inhibits vasoconstriction and reduced aldosterone inhibits water retention. Beta-2 adrenoceptors located in the kidneys and peripheral blood vessels use a similar mechanism to activate cAMP-dependant kinase A to increase smooth muscle contractility. Blocking of the beta-2 adrenoceptor relaxes smooth muscle, leading to vasodilation. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The mean oral bioavailability of pindolol is 87-92%. A 5 mg oral dose reaches a C max of 33.1 ± 5.2 ng/mL, with a T max of 1-2 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of pindolol is approximately 2-3 L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Pindolol is 40% bound to proteins in plasma. Pindolol mainly binds more strongly to alpha-1-acid glycoprotein than it does to serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): 30-40% of a dose of pindolol is not metabolized. The remainder is hydroxylated and subsequently undergoes glucuronidation or sulfate conjugation. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 80% of an oral dose is eliminated in the urine, with 25-40% of the dose as the unchanged parent compound. 6-9% of an intravenous dose is eliminated in the feces. Overall, 60-65% of a dose is eliminated as glucuronide and sulfate metabolites. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half life of pindolol varies from 3-4 hours but can be as high as 30 hours in patients with cirrhosis of the liver. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): In otherwise healthy patients, the systemic clearance of pindolol is 400-500 mL/min. In patients with cirrhosis, the clearance of pindolol varies from 50-300 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Patients experiencing an overdose may experience excessive bradycardia, cardiac failure, hypotension, and bronchospasm. Initiate treatment with symptomatic and supportive measures. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Viskazide, Visken •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-(1H-indol-4-yloxy)-3-(isopropylamino)propan-2-ol 1-(1H-indol-4-yloxy)-3-(propan-2-ylamino)-propan-2-ol 1-(1H-indol-4-yloxy)-3-[(1-methylethyl)amino]propan-2-ol 4-(2-hydroxy-3-isopropylaminopropoxy)-indole Pindolol (common) Pindololum (common)

Do Abaloparatide and Polythiazide interact?

•Drug A: Abaloparatide •Drug B: Polythiazide •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Polythiazide. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •References: 1. Lee CH, Strosberg AM, Carver LA: Antihypertensive drugs: their postural hypotensive effect and their blood pressure lowering activity in conscious normotensive rats. Arch Int Pharmacodyn Ther. 1983 Jan;261(1):90-101. [https://go.drugbank.com/articles/A177104] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Polythiazide is a thiazide diuretic used to decrease edema and decrease blood pressure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): As a thiazide diuretic, Polythiazide inhibits the sodium-chloride symporter which decreases solute reabsorption leading to a retention of water in the urine, as water normally follows solutes. More frequent urination is due to the increased loss of water that has not been retained from the body as a result of a concomitant relationship with sodium loss from the convoluted tubule. The short-term anti-hypertensive action is based on the fact that thiazides decrease preload, decreasing blood pressure •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): As a diuretic, polythiazide inhibits active chloride reabsorption at the early distal tubule via the thiazide-sensitive Na-Cl cotransporter (TSC), resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like polythiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of polythiazide may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Minizide, Renese, Renese-R •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Pramipexole interact?

•Drug A: Abaloparatide •Drug B: Pramipexole •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Pramipexole is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): This drug is indicated for the symptomatic treatment of Parkinson’s disease. This drug can be administered as monotherapy or in conjunction with levodopa. It is also indicated for symptomatic treatment of moderate to severe primary Restless Legs Syndrome (RLS). •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Parkinson's Disease Through the stimulation of dopamine receptors, pramipexole is thought to relieve the symptoms of Parkinson's Disease. The motor symptoms of Parkinson's disease occur partly due to a reduction of dopamine in the substantia nigra of the brain. Dopamine is an essential neurotransmitter that has major effects on motor movements in humans. Restless Legs Syndrome Pramipexole likely restores balance to the dopaminergic system, controlling the symptoms of this condition. Restless legs syndrome is thought to occur, in part, through dysfunction of the dopaminergic system, resulting in unpleasant lower extremity symptoms,. Other effects In addition to the abovementioned effects, animal studies demonstrate that pramipexole blocks dopamine synthesis, release, and turnover. Additionally, this drug is neuroprotective to dopamine neuron degeneration after ischemia or methamphetamine neurotoxicity. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The exact mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown at this time. It is thought, however, that the ability of pramipexole to cause stimulation of the dopamine receptors in the striatum of the brain, a region that receives a vast array of neurological input and is responsible for a wide variety of functions, may be involved. Studies performed in animals show that pramipexole influences striatal neuronal transmission rates following activation of dopamine receptors. Pramipexole is considered a non-ergot dopamine agonist that shows specificity and strong activity at the D2 subfamily of dopamine receptors in vitro, binding selectively and dopamine D2 receptors and showing a preference for the dopamine D3 receptor subtype rather than other subtypes. The clinical significance of this binding specificity is unknown,. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The bioavailability of pramipexole is higher than 90%, indicating a high level of absorption. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): This drug is extensively distributed in the body with a volume of distribution of approximately 500 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): About 15% bound to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): This drug undergoes little metabolism in humans. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The main route of pramipexole elimination, with 90% of a pramipexole dose found in the urine, almost entirely as unchanged drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): About 8.5-12 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Renal clearance is about 400 mL/min, indicating heavy secretion by the renal tubules. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD50 Rat Oral LD 50 >800 mg/kg. Carcinogenicity, mutagenicity, impact on fertility Pramipexole was not found to be carcinogenic in 2-year studies on mice and rats at 0.3, 2.2, and 11 times the maximum recommended human dose (MRHD). No increased incidence of tumors was observed. No mutagenicity was detected in various assays, including the Ames test. Finally, pramipexole given to rat models at a dose of 2.5 mg/kg/day (5 times the maximum recommended human dose), increased estrus cycles and inhibited implantation of a fertilized ovum. Decreased levels of prolactin, a hormone necessary for implantation and maintenance of early pregnancy, were measured. The significance of these findings in humans is unknown. Pregnancy This drug is considered a pregnancy category C drug, showing teratogenic effects in animals. Currently, there no studies of pramipexole in human pregnancy. Animal reproduction studies are not always predictive of human response. This drug should only be used in pregnancy if the potential benefit outweighs the possible fetal risks. Nursing Whether pramipexole is excreted in human milk is unknown. A decision should be made regarding the administration pramipexole during nursing, or whether to discontinue it during nursing, as many drugs are excreted in human milk. The potential exists for risk to the infant if pramipexole is, in fact, excreted in the milk. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Mirapex, Mirapexin, Sifrol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (-)-Pramipexole (S)-N  6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine Pramipexol (common) Pramipexole (common) Pramipexolum (common)

Do Abaloparatide and Prazosin interact?

•Drug A: Abaloparatide •Drug B: Prazosin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Prazosin is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): This drug is indicated for the treatment of hypertension (high blood pressure). Prazosin can be given alone or given with other blood pressure-lowering drugs, including diuretics or beta-adrenergic blocking agents. Prazosin does not negatively impact lung function, and therefore may be used to manage hypertension in patients who are asthmatic or patients with chronic obstructive lung disease (COPD). •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Effects on blood pressure The pharmacodynamic and therapeutic effect of this drug includes is a decrease in blood pressure as well as clinically significant decreases in cardiac output, heart rate, blood flow to the kidney, and glomerular filtration rate. The decrease in blood pressure may occur in both standing and supine positions. Many of the above effects are due to vasodilation of blood vessels caused by prazosin, resulting in decreased peripheral resistance,. Peripheral resistance refers to the level resistance of the blood vessels to blood that flows through them. As the blood vessels constrict (narrow), the resistance increases and as they dilate (widen), and peripheral resistance decreases, lowering blood pressure. Effects on sleep disturbance related to post-traumatic stress disorder (PTSD) Some studies have suggested that this drug improves sleep in patients suffering from insomnia related to nightmares and post-traumatic stress disorder, caused by hyperarousal. This effect likely occurs through the inhibition of adrenergic stimulation found in states of hyperarousal. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Alpha-adrenergic receptors are essential for the regulation of blood pressure in humans. Two types of alpha receptors, alpha 1 and alpha 2, both play a role in regulating blood pressure. Alpha-1 receptors are postsynaptic (located after the nerve junction, or space between a nerve fiber and target tissue). In this case, the target tissue is the vascular smooth muscle. These receptors, when activated, increase blood pressure. Prazosin inhibits the postsynaptic alpha-1 adrenoceptors. This inhibition blocks the vasoconstricting (narrowing) effect of catecholamines (epinephrine and norepinephrine) on the vessels, leading to peripheral blood vessel dilation. Through blood vessel constriction by adrenergic receptor activation, epinephrine and norepinephrine normally act to increase blood pressure. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): After administration of an oral dose, peak plasma concentrations are attained at approximately 3 hours. There is a linear association between the prazosin dose given and plasma concentration at steady state. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): About 0.6 L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Highly bound to proteins with 97% binding to albumin and alpha 1-acid glycoprotein. Prazosin is thought to be mostly (about 80-90%) bound to albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): In animals, prazosin hydrochloride is heavily metabolized. This occurs through liver demethylation and conjugation. Some studies in humans or human cells in vitro show similar prazosin metabolism. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): This drug is mainly excreted in the bile and the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The plasma half-life is about 2-3 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): In patients with congestive heart failure, the clearance of this drug is decreased. Impairment of renal function does not have relevant effects on elimination. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): TDLO, LD50: Oral TDLO (human): 285 μg/kg; Oral TDLO (woman): 10 μg/kg. Oral LD50 (rat): 1950 mg/kg; Intraperitoneal LD50 (rat): 102 mg/kg. Overdose information Accidental ingestion of at least 50 mg of prazosin by a two-year-old child led to severe drowsiness with depressed reflexes. There was no fall in blood pressure, and the child recovered without complication. Use in pregnancy There are no adequate and well-controlled studies determining the safety of prazosin use during pregnancy. It is considered a pregnancy category C drug. Prazosin should be used during pregnancy only in cases where the benefit outweighs the possible risk to the mother and fetus. In specific cases where blood pressure control was emergent during pregnancy, prazosin has been used and no effects on the fetus or neonate were reported. Use in nursing This drug is found excreted in small concentrations in human milk. This drug should be used with caution when used during nursing. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Minipress, Minizide •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine 2-(4-(2-Furoyl)piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline Prazosin (common) Prazosina (common) Prazosine (common) Prazosinum (common)

Do Abaloparatide and Primidone interact?

•Drug A: Abaloparatide •Drug B: Primidone •Severity: MODERATE •Description: Primidone may increase the hypotensive activities of Abaloparatide. •Extended Description: The use of barbiturates may increase hypotension.1,2 Therefore, the concomitant administration of barbiturates and hypotensive agents may lead to dangerous hypotension due to additive effects. •References: 1. Suddock JT, Cain MD: Barbiturate Toxicity . [https://go.drugbank.com/articles/A233155] 2. Roberts I, Sydenham E: Barbiturates for acute traumatic brain injury. Cochrane Database Syst Rev. 2012 Dec 12;12(12):CD000033. doi: 10.1002/14651858.CD000033.pub2. [https://go.drugbank.com/articles/A259951] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Primidone is commonly indicated for the management of grand mal, psychomotor, and focal epileptic seizures. In addition, it has also been studied and utilized as an effective management of essential tremor. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Primidone alters sodium and calcium channel transport, reducing the frequency of nerve firing, which may be responsible for its effect on convulsions and essential tremor. Primidone has a wide therapeutic window as doses of 50-1000mg/day were effective. Patients should be counselled regarding the risk of status epilepticus with abrupt cessation of primidone. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Primidone and its metabolites, phenobarbital and phenylethylmalonamide (PEMA), are active anticonvulsants. Primidone does not directly interact with GABA-A receptors or chloride channels but phenobarbital does. Primidone alters transmembrane sodium and calcium channel transport, reducing the frequency of nerve firing, which may be responsible for the primidone’s effect on convulsions and essential tremor. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Oral primidone is up to 80% bioavailable with a T max if 2-4h. A 500mg oral dose of primidone Reaches a C max of 2.7±0.4µg/mL with a T max of 0.5-7h. Data regarding the AUC of primidone is not readily available. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of primidone is 0.5-0.8L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Primidone is 10.78-13.70% protein bound in serum. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Primidone is metabolized to phenobarbitol and phenylethylmalonamide (PEMA). This metabolism is largely mediated by CYP2C9, CYP2C19, and CYP2E1. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Primidone is 72.9-80.6% recovered in urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half life of primidone is 7-22h in adults, 5-11h in children, and 8-80h in newborns. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Primidone is cleared at a rate of 30mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 in rats is 1500mg/kg and in mice is 280mg/kg. The intraperitoneal LD 50 in rats was 240mg/kg and in mice was 332mg/kg. Patients experiencing a primidone overdose may present with CNS depression, coma, respiratory depression, suppressed reflexes, suppressed response to pain, hypotension, and decreased urine output. Overdose should be treated with symptomatic and supportive treatment, including the removal of unabsorbed drug. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Mysoline •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-deoxyphenobarbital (common) 5-Phenyl-5-ethyl-Hexahydropyrimidine-4,6-dione Primidon (common) Primidona (common) Primidone (common) Primidonum (common)

Do Abaloparatide and Procaine interact?

•Drug A: Abaloparatide •Drug B: Procaine •Severity: MODERATE •Description: Procaine may increase the orthostatic hypotensive activities of Abaloparatide. •Extended Description: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. •References: 1. Cockhill LA, Remick RA: Blood pressure effects of monoamine oxidase inhibitors--the highs and lows. Can J Psychiatry. 1987 Dec;32(9):803-8. [https://go.drugbank.com/articles/A36302] 2. Remick RA, Froese C: Monoamine oxidase inhibitors: clinical review. Can Fam Physician. 1990 Jun;36:1151-5. [https://go.drugbank.com/articles/A36361] 3. Delini-Stula A, Baier D, Kohnen R, Laux G, Philipp M, Scholz HJ: Undesirable blood pressure changes under naturalistic treatment with moclobemide, a reversible MAO-A inhibitor--results of the drug utilization observation studies. Pharmacopsychiatry. 1999 Mar;32(2):61-7. doi: 10.1055/s-2007-979193. [https://go.drugbank.com/articles/A36609] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used as a local anesthetic primarily in oral surgery •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Procaine is an anesthetic agent indicated for production of local or regional anesthesia, particularly for oral surgery. Procaine (like cocaine) has the advantage of constricting blood vessels which reduces bleeding, unlike other local anesthetics like lidocaine. Procaine is an ester anesthetic. It is metabolized in the plasma by the enzyme pseudocholinesterase through hydrolysis into para-aminobenzoic acid (PABA), which is then excreted by the kidneys into the urine. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Procaine acts mainly by inhibiting sodium influx through voltage gated sodium channels in the neuronal cell membrane of peripheral nerves. When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is thus inhibited. The receptor site is thought to be located at the cytoplasmic (inner) portion of the sodium channel. Procaine has also been shown to bind or antagonize the function of N-methyl-D-aspartate (NMDA) receptors as well as nicotinic acetylcholine receptors and the serotonin receptor-ion channel complex. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hydrolysis by plasma esterases to PABA •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): With normal kidney function, the drug is excreted rapidly by tubular excretion. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 7.7 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Novocain •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-Diethylaminoethyl p-aminobenzoate 4-aminobenzoic acid 2-diethylaminoethyl ester Novocaine (common) p-Aminobenzoic acid 2-diethylaminoethyl ester Procaina (common) Procaine (common) Procainum (common) Vitamin H3 (common) β-(diethylamino)ethyl 4-aminobenzoate β-(diethylamino)ethyl p-aminobenzoate

Do Abaloparatide and Procarbazine interact?

•Drug A: Abaloparatide •Drug B: Procarbazine •Severity: MODERATE •Description: Procarbazine may increase the orthostatic hypotensive activities of Abaloparatide. •Extended Description: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. •References: 1. Cockhill LA, Remick RA: Blood pressure effects of monoamine oxidase inhibitors--the highs and lows. Can J Psychiatry. 1987 Dec;32(9):803-8. [https://go.drugbank.com/articles/A36302] 2. Remick RA, Froese C: Monoamine oxidase inhibitors: clinical review. Can Fam Physician. 1990 Jun;36:1151-5. [https://go.drugbank.com/articles/A36361] 3. Delini-Stula A, Baier D, Kohnen R, Laux G, Philipp M, Scholz HJ: Undesirable blood pressure changes under naturalistic treatment with moclobemide, a reversible MAO-A inhibitor--results of the drug utilization observation studies. Pharmacopsychiatry. 1999 Mar;32(2):61-7. doi: 10.1055/s-2007-979193. [https://go.drugbank.com/articles/A36609] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For use with other anticancer drugs for the treatment of stage III and stage IV Hodgkin's disease. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Procarbazine is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Procarbazine is cell-phase specific for the S phase of cell division. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The precise mode of cytotoxic action of procarbazine has not been clearly defined. There is evidence that the drug may act by inhibition of protein, RNA and DNA synthesis. Studies have suggested that procarbazine may inhibit transmethylation of methyl groups of methionine into t-RNA. The absence of functional t-RNA could cause the cessation of protein synthesis and consequently DNA and RNA synthesis. In addition, procarbazine may directly damage DNA. Hydrogen peroxide, formed during the auto-oxidation of the drug, may attack protein sulfhydryl groups contained in residual protein which is tightly bound to DNA. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Procarbazine is rapidly and completely absorbed. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Procarbazine is metabolized primarily in the liver and kidneys. The drug appears to be auto-oxidized to the azo derivative with the release of hydrogen peroxide. The azo derivative isomerizes to the hydrazone, and following hydrolysis splits into a benzylaldehyde derivative and methylhydrazine. The methylhydrazine is further degraded to CO 2 and CH 4 and possibly hydrazine, whereas the aldehyde is oxidized to N-isopropylterephthalamic acid, which is excreted in the urine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 10 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD 50 =785 mg/kg (orally in rats) •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Matulane •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-Methyl-2-(p-(isopropylcarbamoyl)benzyl)hydrazine 2-(p-Isopropylcarbamoylbenzyl)-1-methylhydrazine 4-((2-Methylhydrazino)methyl)-N-isopropylbenzamide N-(1-Methylethyl)-4-((2-methylhydrazino)methyl)benzamide N-4-Isopropylcarbamoylbenzyl-N'-methylhydrazine N-isopropyl-4-[(2-methylhydrazino)methyl]benzamide N-Isopropyl-p-(2-methylhydrazinomethyl)-benzamide N-Isopropyl-α-(2-methylhydrazino)-p-toluamide p-(2-Methylhydrazinomethyl)-N-isopropylbenzamide Procarbazin (common) Procarbazina (common) Procarbazine (common) Procarbazinum (common)

Do Abaloparatide and Propofol interact?

•Drug A: Abaloparatide •Drug B: Propofol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Propofol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used for induction and/or maintenance of anaesthesia and for management of refractory status epilepticus. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Propofol is a sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol produces hypnosis rapidly with minimal excitation, usually within 40 seconds from the start of an injection (the time for one arm-brain circulation). •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The action of propofol involves a positive modulation of the inhibitory function of the neurotransmitter gama-aminobutyric acid (GABA) through GABA-A receptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapid - time to onset of unconsciousness is 15-30 seconds, due to rapid distribution from plasma to the CNS. Distribution is so rapid that peak plasma concentrations cannot be readily measured. Duration of action is 5-10 minutes. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 60 L/kg [healthy adults] •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 95 to 99%, primarily to serum albumin and hemoglobin •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatically metabolized mainly by glucuronidation at the C1-hydroxyl. Hydroxylation of the benzene ring to 4-hydroxypropofol may also occur via CYP2B6 and 2C9 with subsequent conjugation to sulfuric and/or glucuronic acid. Hydroxypropofol has approximately 1/3 of hypnotic activity of propofol. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Initial distribution phase t 1/2α =1.8-9.5 minutes. Second redistirubtion phase t 1/2β =21-70 minutes. Terminal elimination phase t 1/2γ =1.5-31 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 23 - 50 mL/kg/min 1.6 - 3.4 L/min [70 Kg adults] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdosage may increase pharmacologic and adverse effects or cause death. IV LD 50 =53 mg/kg (mice), 42 mg/kg (rats). Oral LD 50 (as a solution in soybean oil)=1230 mg/kg (mice), 600 mg/kg (rats) •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Diprivan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2,6-bis(1-methylethyl)phenol 2,6-Diisopropylphenol Propofol (common) Propofolum (common)

Do Abaloparatide and Propranolol interact?

•Drug A: Abaloparatide •Drug B: Propranolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Propranolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Propranolol is indicated to treat hypertension. Propranolol is also indicated to treat angina pectoris due to coronary atherosclerosis, atrial fibrillation, myocardial infarction, migraine, essential tremor, hypertrophic subaortic stenosis, pheochromocytoma, and proliferating infantile hemangioma. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Propranolol is a beta-adrenergic receptor antagonist used to treat hypertension. Propranolol has a long duration of action as it is given once or twice daily depending on the indication. When patients abruptly stop taking propranolol, they may experience exacerbations of angina and myocardial infarctions. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Propranolol is a nonselective β-adrenergic receptor antagonist. Blocking of these receptors leads to vasoconstriction, inhibition of angiogenic factors like vascular endothelial growth factor (VEGF) and basic growth factor of fibroblasts (bFGF), induction of apoptosis of endothelial cells, as well as down regulation of the renin-angiotensin-aldosterone system. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Patients taking doses of 40mg, 80mg, 160mg, and 320mg daily experienced C max values of 18±15ng/mL, 52±51ng/mL, 121±98ng/mL, and 245±110ng/mL respectively. Propranolol has a T max of approximately 2 hours, though this can range from 1 to 4 hours in fasting patients. Taking propranolol with food does not increase T max but does increase bioavailability. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of propranolol is approximately 4L/kg or 320L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Approximately 90% of propranolol is protein bound in plasma. Other studies have reported ranges of 85-96%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Propranolol undergoes side chain oxidation to α-naphthoxylactic acid, ring oxidation to 4’-hydroxypropranolol, or glucuronidation to propranolol glucuronide. It can also be N-desisopropylated to become N-desisopropyl propranolol. 17% of a dose undergoes glucuronidation and 42% undergoes ring oxidation. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 91% of an oral dose of propranolol is recovered as 12 metabolites in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half-life of propranolol is approximately 8 hours. The plasma half-life of propranolol is 3 to 6 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of propranolol is 2.7±0.03L/h/kg in infants <90 days and 3.3±0.35L/h/kg in infants >90 days. Propranolol clearance increases linearly with hepatic blood flow. Propranolol has a clearance in hypertensive adults of 810mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include hypotension, hypoglycemic seizure, restlessness, euphoria, insomnia. Patients with asthma may develop bronchospasm. In case of overdose, monitor vital signs, mental status, and blood glucose. Treat hypotension with intravenous fluids, bradycardia with atropine, and isoproterenol and aminophylline for bronchospasm. If patients do not respond to intravenous fluids, follow up with glucagon 50-150µg/kg intravenously, then 1-5mg/hour, followed by catecholamines. Dialysis will not be useful as propranolol is highly protein bound. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Hemangeol, Hemangiol, Inderal, Innopran •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-((1-Methylethyl)amino)-3-(1-naphthalenyloxy)-2-propanol 1-(isopropylamino)-3-(1-naphthyloxy)propan-2-ol beta-Propranolol (common) Propanalol (common) Propanolol (common) Propranolol (common) Propranololo (common) Propranololum (common) β-Propranolol

Do Abaloparatide and Quetiapine interact?

•Drug A: Abaloparatide •Drug B: Quetiapine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Quetiapine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Quetiapine is used in the symptomatic treatment of schizophrenia. In addition, it may be used for the management of acute manic or mixed episodes in patients with bipolar I disorder, as a monotherapy or combined with other drugs. It may be used to manage depressive episodes in bipolar disorder. In addition to the above indications, quetiapine is used in combination with antidepressant drugs for the treatment of major depression. Some off-label uses for this drug include the management of post-traumatic stress disorder (PTSD), generalized anxiety disorder, and psychosis associated with Parkinson's disease. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Quetiapine improves the positive and negative symptoms of schizophrenia and major depression by acting on various neurotransmitter receptors, such as the serotonin and dopamine receptors. In bipolar disorder, it improves both depressive and manic symptoms. A note on suicidality in young patients and administration in the elderly Quetiapine can cause suicidal thinking or behavior in children and adolescents and should not be given to children under 10 years of age. It is important to monitor for suicidality if this drug is given to younger patients. In addition, this drug is not indicated for the treatment of psychosis related to dementia due to an increased death rate in elderly patients taking this drug. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Although the mechanism of action of quetiapine is not fully understood, several proposed mechanisms exist. In schizophrenia, its actions could occur from the antagonism of dopamine type 2 (D2) and serotonin 2A (5HT2A) receptors. In bipolar depression and major depression, quetiapine's actions may be attributed to the binding of this drug or its metabolite to the norepinephrine transporter. Additional effects of quetiapine, including somnolence, orthostatic hypotension, and anticholinergic effects, may result from the antagonism of H1 receptors, adrenergic α1 receptors, and muscarinic M1 receptors, respectively. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Quetiapine is rapidly and well absorbed after administration of an oral dose. Steady-state is achieved within 48 hours Peak plasma concentrations are achieved within 1.5 hours. The bioavailability of a tablet is 100%. The steady-state Cmax of quetiapine in Han Chinese patients with schizophrenia after a 300 mg oral dose of the extended released formulation was approximately 467 ng/mL and the AUC at steady-state was 5094 ng·h/mL. Absorption of quetiapine is affected by food, with Cmax increased by 25% and AUC increased by 15%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Quetiapine distributes throughout body tissues. The apparent volume of distribution of this drug is about 10±4 L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The protein binding of quetiapine is 83%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The metabolism of quetiapine occurs mainly in the liver. Sulfoxidation and oxidation are the main metabolic pathways of this drug. According to in vitro studies, cytochrome P450 3A4 metabolizes quetiapine to an inactive sulfoxide metabolite and also participates in the metabolism of its active metabolite, N-desalkyl quetiapine. CYP2D6 also regulates the metabolism of quetiapine. In one study, three metabolites of N-desalkylquetiapine were identified. Two of the metabolites were identified as N-desalkylquetiapine sulfoxide and 7-hydroxy-N-desalkylquetiapine. CYP2D6 has been found to be responsible for metabolism of quetiapine to 7-hydroxy-N-desalkylquetiapine, a pharmacologically active metabolite. Individual differences in CYP2D6 metabolism may be present, which may affect the concentrations of the active metabolite. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After an oral dose of radiolabeled quetiapine, less than 1% of unchanged drug was detected in the urine, suggesting that quetiapine is heavily metabolized. About 73% of a dose was detected in the urine, and about 20% in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The average terminal half-life of quetiapine is about 6-7 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of quetiapine healthy volunteers in the fasted state during a clinical study was 101.04±39.11 L/h. Elderly patients may require lower doses of quetiapine, as clearance in these patients may be reduced by up to 50%. Those with liver dysfunction may also require lower doses. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD50 if quetiapine in rats is 2000 mg/kg. Overdose information Some signs and symptoms of a quetiapine overdose include sedation, drowsiness, tachycardia, and hypotension. Clinical trials demonstrate that overdoses of up to 30 grams of quetiapine did not result in death. A lethal outcome was reported in a clinical trial after an overdose of 13.6 grams of quetiapine. In the case of an acute overdose, ensure to maintain an airway and provide adequate ventilation and oxygenation. Gastric lavage following intubation (if necessary) along with activated charcoal and a laxative may be considered. The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiac monitoring should also take place. A note on QT-interval prolongation in an overdose Postmarketing reports reveal increases in the cardiac QT interval in cases of quetiapine overdose, concomitant illness, and in those taking drugs that increase QT interval or affect electrolyte levels. Note that disopyramide, procainamide, and quinidine may exert additive QT-prolonging effects when administered in patients who have overdosed with quetiapine, and should be avoided. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Seroquel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-[2-(4-Dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol Quetiapina (common) Quétiapine (common) Quetiapine (common) Quetiapinum (common)

Do Abaloparatide and Quinapril interact?

•Drug A: Abaloparatide •Drug B: Quinapril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Quinapril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Quinapril is indicated for the treatment of hypertension and as an adjunct therapy in the treatment of heart failure. Quinapril in combination with hydrochlorothiazide is indicated for the treatment of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Quinapril is a prodrug of an angiotensin converting enzyme (ACE) inhibitor used in the treatment of hypertension or adjunct in the treatment of heart failure. Quinapril has a wide therapeutic window and a long duration of action as it is given in doses of 10-80mg once daily. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Angiotensin II constricts coronary blood vessels and is positively inotropic, which under normal circumstances, would increase vascular resistance and oxygen consumption. This action can eventually lead to myocyte hypertrophy and vascular smooth muscle cell proliferation. Angiotensin II also stimulates production of plasminogen activator inhibitor-1 (PAI-1), increasing the risk of thrombosis. Quinaprilat prevents the conversion of angiotensin I to angiotensin II by inhibition of angiotensin converting enzyme, and also reduces the breakdown of bradykinin. Reduced levels of angiotensin II lead to lower levels of PAI-1, reducing the risk of thrombosis, especially after a myocardial infarction. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Quinapril if 50-80% bioavailable. Quinapril has a T max of <1 hour, while quinaprilat has a T max of 2.5h. The C max of quinaprilat is highly variable but reaches 1526ng/mL with an AUC of 2443ng*h/mL in healthy males given a 10mg dose. A high fat meal reduces the absorption of quinapril by 25-30%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The mean volume of distribution of quinaprilat is 13.9L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Quinapril and the active metabolite quinaprilat are 97% protein bound in plasma. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Quinapril is de-esterified to the active quinaprilat or dehydrated to form the inactive PD109488. PD109488 can undergo O-deethylation to form another inactive metabolite, PD113413. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Quinaprilat is up to 96% eliminated in the urine. The eliminated metabolites PD109488 and PD113413 account for approximately 6% of a dose of quinapril each. A small fraction of the dose recovered in the urine is accounted for by unmetabolized quinapril. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The active metabolite quinaprilat has an elimination half life of 2.3 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of quinaprilat is 68mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 in rats is 3541mg/kg and in mice is 1739mg/kg. Patients experiencing an overdose may present with symptoms of severe hypotension. Due to the extensive protein binding of quinapril and the active metabolite quinaprilat, hemodialysis is not expected to remove the drug from circulation. Treat patients with symptomatic and supportive measures, including normal saline infusions to restore normal blood pressure. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Accupril, Accuretic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Ramipril interact?

•Drug A: Abaloparatide •Drug B: Ramipril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Ramipril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the management of mild to severe hypertension. May be used to reduce cardiovascular mortality following myocardial infarction in hemodynamically stable individuals who develop clinical signs of congestive heart failure within a few days following myocardial infarction. To reduce the rate of death, myocardial infarction and stroke in individuals at high risk of cardiovascular events. May be used to slow the progression of renal disease in individuals with hypertension, diabetes mellitus and microalubinuria or overt nephropathy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Ramipril is an ACE inhibitor similar to benazepril, fosinopril and quinapril. It is an inactive prodrug that is converted to ramiprilat in the liver, the main site of activation, and kidneys. Ramiprilat confers blood pressure lowing effects by antagonizing the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain the effects of ramiprilat by causing increased vasodilation and decreased blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Ramipril inhibits the RAAS system by binding to and inhibiting ACE thereby preventing the conversion of angiotensin I to angiotensin II. As plasma levels of angiotensin II fall, less activation of the G-protein coupled receptors angiotensin receptor I (AT 1 R) and angiotensin receptor II (AT 2 R) occurs. AT 1 R mediates vasoconstriction, inflammation, fibrosis, and oxidative stress through a variety of signaling pathways. These include G q coupling to the inositol triphosphate pathway, activation of phospholipases C, A 2, and D which contribute to eicosanoid production, activation of Ca -dependent and MAP kinases, G i and G 12/13, and eventual activation of the Jak/STAT pathway leading to cell growth and production of extracellular matrix components. AT 1 R activation also leads to increased activity of membrane-bound NADH/NADPH oxidase which contributes to production of reactive oxygen species. Decreased activation of this receptor mediates the renoprotective, antihypertensive, and cardioprotective effects of ramipril by reducing inflammation and vasoconstriction. AT 2 R acts in opposition to the effects of AT 1 R by activating phosphotyrosine phosphatases which inhibit MAP kinases, inhibiting Ca channel opening, and stimulating cGMP and nitric oxide production leading to vasodilation. These counteracting effects are shared by the Mas receptor which is activated by Ang(1-7), a subtype of angiotensin produced by plasma esterases from AngI or by ACE2 from AngII produced through a secondary pathway by tonin and cathepsin G. Ang(1-7) also activates AT 2 R although the bulk of its effect is mediated by MasR. ACE is also responsible for the breakdown of bradykinin. The resulting buildup of bradykinin due to ACE inhibition is thought to mediate the characteristic dry-cough as a side effect of ACE inhibitor medications. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The extent of absorption is at least 50-60%.. Food decreases the rate of absorption from the GI tract without affecting the extent of absorption. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when oral administration was compared to intravenous administration. The serum concentration of ramiprilat was unchanged when capsules were opened and the contents dissolved in water, dissolved in apple juice, or suspended in apple sauce. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Protein binding of ramipril is about 73% and that of ramiprilat about 56%. Protein binding is independent of concentration over the range of 0.1μg/mL-10μg/mL •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic metabolism accounts for 75% of total ramipril metabolism. 25% of hepatic metabolism produces the active metabolite ramiprilat via liver esterase enzymes. 100% of renal metabolism converts ramipril to ramiprilat. Other metabolites, diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, are inactive. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following oral administration, about 60% of the dose is eliminated in the urine as unchanged ramipril (<2%) and its metabolites. About 40% of the dose is found in the feces, representing both unabsorbed drug and drugs and metabolites eliminated via biliary excretion. The urinary excretion of ramipril may be reduced in patients with impaired renal function. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Plasma concentrations of ramiprilat decline in a triphasic manner. Initial rapid decline represents distribution into tissues and has a half life of 2-4 hours. The half life of the apparent elimination phase is 9-18 hours, which is thought to represent clearance of free drug. The half-life of the terminal elimination phase is > 50 hours and thought to represent clearance of drug bound to ACE due to its slow dissociation. The half life of ramiprilat after multiple daily doses (MDDs) is dose-dependent, ranging from 13-17 hours with 5-10 mg MDDs to 27-36 hours for 2.5 mg MDDs. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The renal clearance of ramipril and ramiprilat was reported to be 7.2 and 77.4 mL/min/1.73m. The mean renal clearance of ramipril and ramiprilat is reported to be 10.7 and 126.8 mL/min in healthy elderly patients with normal renal function, additionally the Cmax of ramiprilat is approximately 20% higher in this population. While the pharmacokinetics of ramipril appear unaffected by reduced renal function, the plasma concentration and half-life of ramiprilat are increased. In patient's with hepatic failure the concentration of ramipril is initially increased while the tmax of ramiprilat is prolonged due to a reduced ability to metabolize the drug. However, steady state concentrations of ramiprilat are the same in hepatic failure as in healthy patients. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose may include excessive peripheral vasodilation (with marked hypotension and shock), bradycardia, electrolyte disturbances, and renal failure. Cases of ACE inhibitor induced hepatotoxicity have been reported in humans and presented as acute jaundice and elevated liver enzymes. Removal of the ACE inhbitor resulted in a decline in liver enzymes and re-challenge produced a subsequent increase. There were no observed tumerogenic effects at chronic doses up to 500mg/kg/day to rats for 24 months or at doses up to 1000mg/kg/day to mice for 18 months. For both species doses were administered by gavage and equivalent to 200 time the maximum recommended human exposure based on body surface area. No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites of ramipril also produced negative results in the Ames test. No effects on fertility were seen in rats at doses up to 500mg/kg/day. No teratogenicity was observed in rats and cynomolgus monkeys at doses 400 times the maximum recommended human exposure nor in rabbites at 2 times the maximum recommended human exposure. LD 50 10 g/kg (rat). LD 50 10.5 g/kg (mouse). LD 50 1 g/kg (dog). •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Altace, Altace HCT •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (2S-(1(R*(R*)),2alpha,3abeta,6abeta))-1-(2-((1-(Ethoxycarbonyl)-3-phenylpropyl)amino)-1-oxopropyl)octahydrocyclopenta(b)pyrrole-2-carboxylic acid Ramipril (common) Ramiprilum (common)

Do Abaloparatide and Rasagiline interact?

•Drug A: Abaloparatide •Drug B: Rasagiline •Severity: MODERATE •Description: Rasagiline may increase the orthostatic hypotensive activities of Abaloparatide. •Extended Description: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. •References: 1. Cockhill LA, Remick RA: Blood pressure effects of monoamine oxidase inhibitors--the highs and lows. Can J Psychiatry. 1987 Dec;32(9):803-8. [https://go.drugbank.com/articles/A36302] 2. Remick RA, Froese C: Monoamine oxidase inhibitors: clinical review. Can Fam Physician. 1990 Jun;36:1151-5. [https://go.drugbank.com/articles/A36361] 3. Delini-Stula A, Baier D, Kohnen R, Laux G, Philipp M, Scholz HJ: Undesirable blood pressure changes under naturalistic treatment with moclobemide, a reversible MAO-A inhibitor--results of the drug utilization observation studies. Pharmacopsychiatry. 1999 Mar;32(2):61-7. doi: 10.1055/s-2007-979193. [https://go.drugbank.com/articles/A36609] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of the signs and symptoms of idiopathic Parkinsons disease as initial monotherapy and as adjunct therapy to levodopa. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Rasagiline is a propargylamine and an irreversible inhibitor of monoamine oxidase (MAO). MAO, a flavin-containing enzyme, regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. It is classified into two major molecular species, A and B, and is localized in mitochondrial membranes throughout the body in nerve terminals, brain, liver and intestinal mucosa. MAO-A is found predominantly in the GI tract and liver, and regulates the metabolic degradation of circulating catecholamines and dietary amines. MAO-B is the major form in the human brain and is responsible for the regulation of the metabolic degradation of dopamine and phenylethylamine. In ex vivo animal studies in brain, liver and intestinal tissues rasagiline was shown to be a potent,selective, and irreversible monoamine oxidase type B (MAO-B) inhibitor. At the recommended therapeutic doses, Rasagiline was also shown to be a potent and irreversible inhibitor of MAO-B in platelets. The selectivity of rasagiline for inhibiting only MAO-B (and not MAO-A) in humans and the sensitivity to tyramine during rasagiline treatment at any dose has not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The precise mechanisms of action of rasagiline is unknown. One mechanism is believed to be related to its MAO-B inhibitory activity, which causes an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline's beneficial effects seen in models of dopaminergic motor dysfunction. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rasagiline is rapidly absorbed following oral administration. The absolute bioavailability of rasagiline is about 36%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 87 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Plasma protein binding ranges from 88-94% with mean extent of binding of 61-63% to human albumin over the concentration range of 1-100 ng/ml. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP 1A2 being the major isoenzyme involved in rasagiline metabolism. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway. After oral administration of 14C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Rasagiline has a mean steady-state half life of 3 hours but there is no correlation of pharmacokinetics with its pharmacological effect because of its irreversible inhibition of MAO-B. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Azilect •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (1R)-N-propargylindan-1-amine (R)-indan-1-yl-prop-2-ynyl-amine (R)-N-2-Propynyl-1-indanamine RAS Rasagilina (common) Rasagiline (common)

Do Abaloparatide and Remifentanil interact?

•Drug A: Abaloparatide •Drug B: Remifentanil •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Remifentanil is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For use during the induction and maintenance of general anesthesia. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Remifentanil is an opioid agonist with rapid onset and peak effect and ultra-short duration of action. The opioid activity of remifentanil is antagonized by opioid antagonists such as naloxone. The analgesic effects of remifentanil are rapid in onset and offset. Its effects and side effects are dose dependent and similar to other opioids. Remifentanil in humans has a rapid blood-brain equilibration half-time of 1 ± 1 minutes (mean ± SD) and a rapid onset of action. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Remifentanil is a µ-opioid agonist with rapid onset and peak effect, and short duration of action. The µ-opioid activity of remifentanil is antagonized by opioid antagonists such as naloxone. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 350 mL/kg 452 ± 144 mL/kg [neonates] 223 ± 30.6 mL/kg [adolescents] •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 70% (bound to plasma proteins) •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): By hydrolysis of the propanoic acid-methyl ester linkage by nonspecific blood and tissue esterases. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Remifentanil is an esterase-metabolized opioid. The carboxylic acid metabolite is essentially inactive (1/4600 as potent as remifentanil in dogs) and is excreted by the kidneys with an elimination half-life of approximately 90 minutes. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 1-20 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 40 mL/min/kg [young, healthy adults] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Ultiva •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Rilmenidine interact?

•Drug A: Abaloparatide •Drug B: Rilmenidine •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Rilmenidine. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •References: 1. Lee CH, Strosberg AM, Carver LA: Antihypertensive drugs: their postural hypotensive effect and their blood pressure lowering activity in conscious normotensive rats. Arch Int Pharmacodyn Ther. 1983 Jan;261(1):90-101. [https://go.drugbank.com/articles/A177104] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Riociguat interact?

•Drug A: Abaloparatide •Drug B: Riociguat •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Riociguat. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Riociguat is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class. Riociguat is indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening. Efficacy was shown in patients on Riociguat monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominately patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%). •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation. Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway. Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC via a different binding site, independently of NO. Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The pharmacokinetics of riociguant are dose proportional from 0.5 mg to 2.5 mg. The absolute bioavailability is approximately 94%. After oral administration, peak plasma concentrations were achieved within 1.5 hours. Food does not affect the bioavailability of riociguat. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Volume of distribution at steady state = 30 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 95% with serum albumin and alpha-1–acidic glycoprotein being the main binding components. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The active metabolite (M1) of riociguat is 1/3 to 1/10 as potent as riociguat. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Riociguat is eliminated in the urine (40%) and feces (53%), largely as metabolites. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): About 12 hours in patients and 7 hours in healthy subjects. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): EMBRYO-FETAL TOXICITY Do not administer Riociguat to a pregnant female because it may cause fetal harm. Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception. For all female patients, Riociguat is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Adempas •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Methyl N-[4,6-Diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methyl-carbaminate Riociguat (common) Riociguatum (common)

Do Abaloparatide and Risperidone interact?

•Drug A: Abaloparatide •Drug B: Risperidone •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Risperidone. •Extended Description: Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. As clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive medication, co-administration with agents known to cause hypotension may result in an additive risk for developing a decrease in blood pressure. •References: 1. Wilson MP, Nordstrom K, Hopper A, Porter A, Castillo EM, Vilke GM: Risperidone in the Emergency Setting is Associated with More Hypotension in Elderly Patients. J Emerg Med. 2017 Nov;53(5):735-739. doi: 10.1016/j.jemermed.2017.06.026. Epub 2017 Oct 5. [https://go.drugbank.com/articles/A34886] 2. Himstreet JE, Daya M: Hypotension and orthostasis following a risperidone overdose. Ann Pharmacother. 1998 Feb;32(2):267. doi: 10.1345/aph.17168. [https://go.drugbank.com/articles/A37405] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Risperidone is indicated for the treatment of schizophrenia and irritability associated with autistic disorder. It is also indicated as monotherapy, or adjunctly with lithium or valproic acid, for the treatment of acute mania or mixed episodes associated with bipolar I disorder. Risperidone is additionally indicated in Canada for the short-term symptomatic management of aggression or psychotic symptoms in patients with severe dementia of the Alzheimer type unresponsive to nonpharmacological approaches. Risperidone is also used off-label for a number of conditions including as an adjunct to antidepressants in treatment-resistant depression. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): The primary action of risperidone is to decrease dopaminergic and serotonergic pathway activity in the brain, therefore decreasing symptoms of schizophrenia and mood disorders. Risperidone has a high binding affinity for serotonergic 5-HT2A receptors when compared to dopaminergic D2 receptors in the brain. Risperidone binds to D2 receptors with a lower affinity than first-generation antipsychotic drugs, which bind with very high affinity. A reduction in extrapyramidal symptoms with risperidone, when compared to its predecessors, is likely a result of its moderate affinity for dopaminergic D2 receptors. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Though its precise mechanism of action is not fully understood, current focus is on the ability of risperidone to inhibit the D2 dopaminergic receptors and 5-HT2A serotonergic receptors in the brain. Schizophrenia is thought to result from an excess of dopaminergic D2 and serotonergic 5-HT2A activity, resulting in overactivity of central mesolimbic pathways and mesocortical pathways, respectively. D2 dopaminergic receptors are transiently inhibited by risperidone, reducing dopaminergic neurotransmission, therefore decreasing positive symptoms of schizophrenia, such as delusions and hallucinations. Risperidone binds transiently and with loose affinity to the dopaminergic D2 receptor, with an ideal receptor occupancy of 60-70% for optimal effect. Rapid dissociation of risperidone from the D2 receptors contributes to decreased risk of extrapyramidal symptoms (EPS), which occur with permanent and high occupancy blockade of D2 dopaminergic receptors. Low-affinity binding and rapid dissociation from the D2 receptor distinguish risperidone from the traditional antipsychotic drugs. A higher occupancy rate of D2 receptors is said to increase the risk of extrapyramidal symptoms and is therefore to be avoided. Increased serotonergic mesocortical activity in schizophrenia results in negative symptoms, such as depression and decreased motivation. The high-affinity binding of risperidone to 5-HT2A receptors leads to a decrease in serotonergic activity. In addition, 5-HT2A receptor blockade results in decreased risk of extrapyramidal symptoms, likely by increasing dopamine release from the frontal cortex, and not the nigrostriatal tract. Dopamine level is therefore not completely inhibited. Through the above mechanisms, both serotonergic and D2 blockade by risperidone are thought to synergistically work to decrease the risk of extrapyramidal symptoms. Risperidone has also been said to be an antagonist of alpha-1 (α1), alpha-2 (α2), and histamine (H1) receptors. Blockade of these receptors is thought to improve symptoms of schizophrenia, however the exact mechanism of action on these receptors is not fully understood at this time. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of risperidone is approximately 1 to 2 L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Risperidone and its active metabolite, 9-hydroxyrisperidone, are ~88% and ~77% protein-bound in human plasma, respectively. They each bind to both serum albumin and alpha-1-acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Extensively metabolized by hepatic cytochrome P450 2D6 isozyme to 9-hydroxyrisperidone (i.e. paliperidone ), which has approximately the same receptor binding affinity as risperidone. Hydroxylation is dependent on debrisoquine 4-hydroxylase and metabolism is sensitive to genetic polymorphisms in debrisoquine 4-hydroxylase. Risperidone also undergoes N-dealkylation to a lesser extent. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Risperidone is extensively metabolized in the liver. In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives are prolonged compared to young healthy subjects. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 3 hours in extensive metabolizers Up to 20 hours in poor metabolizers •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Risperidone is cleared by the kidneys. Clearance is decreased in the elderly and those with a creatinine clearance (ClCr) between 15-59 mL/min, in whom clearance is decreased by approximately 60%. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include lethargy, dystonia/spasm, tachycardia, bradycardia, and seizures. LD 50 =57.7 mg/kg (rat, oral) and 34 mg/kg (rat, intravenous). •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Perseris, Risperdal, Rykindo, Uzedy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Ropinirole interact?

•Drug A: Abaloparatide •Drug B: Ropinirole •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Ropinirole is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of the signs and symptoms of Parkinson's disease and for the treatment of primary moderate-severe restless legs syndrome. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Effects on Parkinson's and restless leg syndrome This drug promotes the relief or improvement of symptoms of Parkinson's or restless leg syndrome by stimulatory actions on dopamine receptors, which regulate movement. Effects on blood pressure Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired abilities in regulating blood pressure with resulting orthostatic hypotension, especially with patients undergoing dose escalation. In some patients in clinical studies, blood pressure changes were associated with orthostatic symptoms, bradycardia, and, in one case in a healthy volunteer, transient sinus arrest accompanied by syncope. The mechanism of orthostatic hypotension caused by ropinirole is assumed to be due to a D2-mediated blunting of noradrenergic response to a standing position, followed by a decrease in peripheral vascular resistance. Nausea is also a frequent symptom which accompanies orthostatic signs and symptoms. Effects on prolactin At oral doses as low as 0.2 mg, ropinirole suppressed serum prolactin concentrations in healthy male volunteers. Ropinirole had no dose-related effect on ECG wave form and rhythm in young, healthy, male volunteers in the range of 0.01 to 2.5 mg. Effects on QT interval Ropinirole had no dose- or exposure-related effect on average QT intervals in healthy male and female volunteers at doses up to 4 mg/day. The effect of ropinirole on QTc intervals at higher exposures reached either due to drug interactions, hepatic dysfunction, or at higher doses has not been adequately evaluated. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Ropinirole is a non-ergoline dopamine agonist. Ropinirole has the highest affinity at the D3 receptors, which are concentrated in the limbic areas of the brain and may be responsible for some of the neuropsychiatric effects. The exact mechanism of action of ropinirole as a treatment for Parkinson’s disease is unknown, however, it is believed to be related to its ability to selectively stimulate dopamine D2 receptors within the caudate-putamen system in the brain. This system affects body movement. Negligible affinity is seen for ropinirole at α2 adrenoreceptors in the periphery and 5HT-1 receptor. Ropinirole has no affinity at the D1-like receptors, benzodiazepine or GABA receptors. The precise mechanism of action of ropinirole as a treatment for Restless Legs Syndrome is unknown, however, it is believed to be related to its ability to stimulate dopamine receptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1 to 2 hours,. Absolute bioavailability was 45% to 55%, suggesting approximately 50% hepatic first-pass effect. The bioavailability of ropinirole prolonged release compared to the immediate release tablets is about 100%. Ingestion of food does not affect the absorption of ropinirole, although its Tmax was increased by 2.5 hours and its Cmax was reduced by approximately 25% when the drug is taken with a high-fat meal. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Ropinirole is found to be widely distributed throughout the body, with an apparent volume of distribution of 7.5 L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 40% bound to plasma proteins with a blood-to-plasma ratio of 1:1. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Ropinirole is heavily metabolized by the liver. The most important metabolic pathways are N­ despropylation and hydroxylation to form the N-despropyl metabolite and hydroxy metabolites, both of which are inactive. The N-despropyl metabolite is then converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxy metabolites. Following this process, the hydroxy metabolite of ropinirole is glucuronidated at a rapid rate. In vitro studies show that the major cytochrome P450 enzyme involved in the metabolism of ropinirole is CYP1A2,. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The majority of the absorbed dose is cleared by the liver. In clinical trials, more than 88% of a radiolabeled dose was recovered in urine. Less than 10% of the administered dose is excreted as unchanged drug in urine. N-despropyl ropinirole is the major metabolite found in the urine (40%), followed by the carboxylic acid metabolite (10%), and the glucuronide of the hydroxy metabolite (10%). •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Approximately 6 hours,. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of ropinirole after oral administration is 47 L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdose Symptoms of overdose include agitation, chest pain, confusion, drowsiness, facial muscle movements, grogginess, increased jerkiness of movement, symptoms of low blood pressure (dizziness, light-headedness)upon standing, nausea, and vomiting. Carcinogenicity Two-year carcinogenicity studies of ropinirole were performed on animal models at oral doses of 5, 15, and 50 mg/kg/day and in rats at oral doses of 1.5, 15, and 50 mg/kg/day. There was an increase in testicular Leydig cell adenomas at all doses tested in rats. The hormonal mechanisms thought to be involved in the development of these tumors in rats are not considered relevant to humans. In mice, there was an increase in benign uterine endometrial polyps at a dose of 50 mg/kg/day. The highest dose not associated with this observation (15 mg/kg/day) is three times the maximum recommended human dose on a mg/m2 basis. Mutagenesis Ropinirole was not found to be mutagenic or clastogenic during in vitro assays, or in the in vivo mouse micronucleus test. Effects on reproduction When given to female rats prior to and during mating and throughout pregnancy, ropinirole led to disruption of implantation at oral doses of 20 mg/kg/day (8 times the MRHD on a mg/m2 basis) or higher. This effect in rats is believed to be due to the prolactin-lowering effects of ropinirole. Use in Pregnancy Pregnancy Category C. There are no sufficient and well-controlled studies done in pregnant women. In animal reproduction studies, ropinirole has demonstrated adverse effects on embryo-fetal development, including teratogenicity. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Requip •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Ropivacaine interact?

•Drug A: Abaloparatide •Drug B: Ropivacaine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Ropivacaine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Ropivacaine is indicated in adult patients for the induction of regional or local anesthesia for surgery or acute pain management. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): In contrast to most other local anesthetics, the presence of epinephrine does not affect the time of onset, duration of action, or the systemic absorption of ropivacaine. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Local anesthetics like ropivacaine block the generation and conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. Specifically, they block the sodium channel and decrease chances of depolarization and consequent action potentials. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Ropivacaine pharmacokinetics are highly dependent on the dose, route of administration, and patient condition. Following epidural administration ropivacaine undergoes complete and biphasic absorption. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Following intravascular infusion, ropivacaine has a steady-state volume of distribution of 41 ± 7 liters. Ropivacaine is able to readily cross the placenta. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Ropivacaine is 94% protein-bound in plasma, primarily to α1-acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Ropivacaine undergoes extensive metabolism, primarily via CYP1A2-mediated aromatic hydroxylation to 3-OH-ropivacaine. The main metabolites excreted in the urine are the N-dealkylated metabolite (PPX) and 3-OH-ropivacaine. Other identified metabolites include 4-OH-ropivacaine, the 3-hydroxy-N-dealkylated (3-OH-PPX) and 4-hydroxy-N-dealkylated (4-OH-PPX) metabolites, and 2-hydroxy-methyl-ropivacaine (which has been identified but not quantified). Unbound PPX, 3-hydroxy-, and 4-hydroxy-ropivacaine have demonstrated pharmacological activity in animal models less than that of ropivacaine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following intravenous administration, 86% of the administered dose of ropivacaine is excreted in the urine, 1% of which comprises unchanged parent drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean terminal half-life of ropivacaine is 1.8 ± 0.7 hours after intravascular administration and 4.2 ± 1 hour after epidural administration. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Following intravenous administration, ropivacaine has a mean plasma clearance of 387 ± 107 mL/min, an unbound plasma clearance of 7.2 ± 1.6 L/min, and a renal clearance of 1 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): High systemic doses of ropivacaine can result in central nervous system (CNS) and cardiovascular effects, with the CNS effects usually occurring at lower blood plasma concentrations and additional cardiovascular effects occurring at higher concentrations (although cardiovascular collapse may occur at lower concentrations). CNS effects include CNS excitation involving nervousness, tingling around the mouth, tinnitus, tremor, dizziness, blurred vision, and seizures. CNS depressant effects may follow, associated with drowsiness, loss of consciousness, respiratory depression and apnea. Cardiovascular events may be caused by hypoxemia secondary to respiratory depression and include hypotension, bradycardia, arrhythmias, and/or cardiac arrest. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Naropin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-(−)-1-propyl-2',6'-pipecoloxylidide (S)-ropivacaine (common) L-N-n-propylpipecolic acid-2,6-xylidide Ropivacaina (common) Ropivacaine (common) Ropivacainum (common)

Do Abaloparatide and Rotigotine interact?

•Drug A: Abaloparatide •Drug B: Rotigotine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Rotigotine. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For use/treatment in neurologic disorders and parkinson's disease as well as moderate-to-severe primary Restless Legs Syndrome. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Rotigotine is an agonist at all 5 dopamine receptor subtypes (D1-D5) but binds to the D3 receptor with the highest affinity. It is also an antagonist at α-2-adrenergic receptors and an agonist at the 5HT1A receptors. Rotigotine also inhibits dopamine uptake and prolactin secretion. There is no indication of a QT/QTc prolonging effect of Neupro in doses up to 24 mg/24 hours. The effects of Neupro at doses up to 24 mg/24 hours (supratherapeutic doses) on the QT/QTc interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg IV, single dose) parallel-group trial with an overall treatment period of 52 days in male and female patients with advanced-stage Parkinson's disease. Assay sensitivity was confirmed by significant QTc prolongation by moxifloxacin. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Rotigotine, a member of the dopamine agonist class of drugs, is delivered continuously through the skin (transdermal) using a silicone-based patch that is replaced every 24 hours. A dopamine agonist works by activating dopamine receptors in the body, mimicking the effect of the neurotransmitter dopamine. The precise mechanism of action of rotigotine as a treatment for Restless Legs Syndrome is unknown but is thought to be related to its ability to stimulate dopamine •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bioavailability varies depending on the application site. Differences in bioavailability were very small between the abdomen and hip (<1%). In contrast, the shoulder and thigh had a very large different in measured bioavailability (46%), with the shoulder showing the higher value. Tmax, 8 mg dose = 15 - 18 hours (it take approximately 3 hours until rotigotine reaches detectable levels in the plasma). The peak concentration cannot be observered. Steady state is reached in 2-3 days. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The weight normalized apparent volume of distribution, (Vd/F), in humans is approximately 84 L/kg after repeated dose administration. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 92% in vitro and 89.5% in vivo. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic (CYP-mediated). Rotigotine is extensively and rapidly metabolized by conjugation and N-dealkylation. After intravenous dosing the predominant metabolites in human plasma are sulfate conjugates of rotigotine, glucuronide conjugates of rotigotine, sulfate conjugates of the N-despropyl-rotigotine and conjugates of N-desthienylethyl-rotigotine. Multiple CYP isoenzymes, sulfotransferases and two UDP-glucuronosyltransferases catalyze the metabolism of rotigotine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Urine (71%), Fecal (23%). Most of rotigotine that is excreted in the urine is in the form of inactive conjugates. Unchanged drug made up less <1%. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): After removal of the patch, plasma levels decreased with a terminal half-life of 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The most likely symptoms of overdose would be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hypotension, involuntary movements, hallucinations, confusion, convulsions, and other signs of excessive dopaminergic stimulation. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Neupro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (6S)-6-(propyl(2-(2-thienyl)ethyl)amino)-5,6,7,8-tetrahydro-1-naphthalenol Rotigotina (common) Rotigotine (common)

Do Abaloparatide and Safinamide interact?

•Drug A: Abaloparatide •Drug B: Safinamide •Severity: MODERATE •Description: Safinamide may increase the orthostatic hypotensive activities of Abaloparatide. •Extended Description: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. •References: 1. Cockhill LA, Remick RA: Blood pressure effects of monoamine oxidase inhibitors--the highs and lows. Can J Psychiatry. 1987 Dec;32(9):803-8. [https://go.drugbank.com/articles/A36302] 2. Remick RA, Froese C: Monoamine oxidase inhibitors: clinical review. Can Fam Physician. 1990 Jun;36:1151-5. [https://go.drugbank.com/articles/A36361] 3. Delini-Stula A, Baier D, Kohnen R, Laux G, Philipp M, Scholz HJ: Undesirable blood pressure changes under naturalistic treatment with moclobemide, a reversible MAO-A inhibitor--results of the drug utilization observation studies. Pharmacopsychiatry. 1999 Mar;32(2):61-7. doi: 10.1055/s-2007-979193. [https://go.drugbank.com/articles/A36609] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Safinamide is indicated as an add-on treatment to levodopa with or without other medicines for Parkinson’s disease •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Safinamide is a unique molecule with multiple mechanisms of action and a very high therapeutic index. It combines potent, selective, and reversible inhibition of MAO-B with blockade of voltage-dependent Na+ and Ca2+ channels and inhibition of glutamate release. Safinamide has neuroprotective and neurorescuing effects in MPTP-treated mice, in the rat kainic acid, and in the gerbil ischemia model. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapid with peak plasma concentrations ranging from 2 to 4 h, total bioavailability is 95%. Food prolonged the rate and did not affect the extent of absorption of safinamide. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 1.8 litres/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 88–90% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The principal step is mediated by amidases which have not been identified, and produces safinamide acid. It is also metabolized to O-debenzylated safinamide and N-delkylated amine. The N-dealkylated amine is then oxidized to a carboxylic acid and finally glucuronidated. Dealkylation reactions are mediated by cytochrome P450s (CYPs), especially CYP3A4. Safinamide acid binds to organic anion transporter 3 (OAT3), but no clinical relevance of this interaction has been determined. Safinamide also binds to ABCG2 transiently. No other transporter affinities have been found in preliminary studies. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 76% renal, 1.5% faeces •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 22 h •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): total oral clearance of plasma, which accounts for parent safinamide as well as metabolites, was on average only 17.53 ± 2.71 ml/h × kg •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): uncontrolled involuntary movement, falls, nausea, and trouble sleeping or falling asleep (insomnia) Patients who have an overdose may experience hypertension (high blood pressure), orthostatic hypotension, hallucinations, psychomotor agitation, nausea, vomiting, and dyskinesia. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Xadago •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Secobarbital interact?

•Drug A: Abaloparatide •Drug B: Secobarbital •Severity: MODERATE •Description: Secobarbital may increase the hypotensive activities of Abaloparatide. •Extended Description: The use of barbiturates may increase hypotension.1,2 Therefore, the concomitant administration of barbiturates and hypotensive agents may lead to dangerous hypotension due to additive effects. •References: 1. Suddock JT, Cain MD: Barbiturate Toxicity . [https://go.drugbank.com/articles/A233155] 2. Roberts I, Sydenham E: Barbiturates for acute traumatic brain injury. Cochrane Database Syst Rev. 2012 Dec 12;12(12):CD000033. doi: 10.1002/14651858.CD000033.pub2. [https://go.drugbank.com/articles/A259951] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the Short-term treatment of intractable insomnia for patients habituated to barbiturates •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Secobarbital, a barbiturate, is used for the induction of anesthesia prior to the use of other general anesthetic agents and for induction of anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli. Little analgesia is conferred by barbiturates; their use in the presence of pain may result in excitation. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Secobarbital binds at a distinct binding site associated with a Cl ionopore at the GABA A receptor, increasing the duration of time for which the Cl ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Barbiturates are metabolized primarily by the hepatic microsomal enzyme system, and the metabolic products are excreted in the urine and, less commonly, in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of an overdose typically include sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgment, drowsiness or coma, shallow breathing, staggering, and in severe cases coma and death. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Seconal Sodium •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (±)-secobarbital 5-(1-methylbutyl)-5-(2-propenyl)-2,4,6(1H,3H,5H)-pyrimidinetrione 5-allyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione 5-allyl-5-(1-methylbutyl)barbituric acid 5-allyl-5-(1-methylbutyl)pyrimidine-2,4,6(1H,3H,5H)-trione Quinalbarbitone (common) Secobarbital (common) Secobarbitalum (common) Secobarbitone (common)

Do Abaloparatide and Selegiline interact?

•Drug A: Abaloparatide •Drug B: Selegiline •Severity: MODERATE •Description: Selegiline may increase the orthostatic hypotensive activities of Abaloparatide. •Extended Description: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. •References: 1. Cockhill LA, Remick RA: Blood pressure effects of monoamine oxidase inhibitors--the highs and lows. Can J Psychiatry. 1987 Dec;32(9):803-8. [https://go.drugbank.com/articles/A36302] 2. Remick RA, Froese C: Monoamine oxidase inhibitors: clinical review. Can Fam Physician. 1990 Jun;36:1151-5. [https://go.drugbank.com/articles/A36361] 3. Delini-Stula A, Baier D, Kohnen R, Laux G, Philipp M, Scholz HJ: Undesirable blood pressure changes under naturalistic treatment with moclobemide, a reversible MAO-A inhibitor--results of the drug utilization observation studies. Pharmacopsychiatry. 1999 Mar;32(2):61-7. doi: 10.1055/s-2007-979193. [https://go.drugbank.com/articles/A36609] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Monotherapy for initial treatment of Parkinson's disease, as well as an adjunct therapy in patients with a decreased response to levodopa/carbadopa. Also used for the palliative treatment of mild to moderate Alzheimer's disease and at higher doses, for the treatment of depression. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Dopamine is an essential chemical that occurs in many parts of the body. It is the premature degradation of dopamine that results in the symptoms of Parkinson's disease. Monoamine oxidase (MAO) is an enzyme which accelerates the breakdown of dopamine. Selegiline can prolong the effects of dopamine in the brain by preventing its breakdown through seletively blocking MAO-B. It also may prevent the removal of dopamine between nerve endings and enhance release of dopamine from nerve cells. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Although the mechanisms for selegiline's beneficial action in the treatment of Parkinson's disease are not fully understood, the selective, irreversible inhibition of monoamine oxidase type B (MAO-B) is thought to be of primary importance. MAO-B is involved in the oxidative deamination of dopamine in the brain. Selegiline binds to MAO-B within the nigrostriatal pathways in the central nervous system, thus blocking microsomal metabolism of dopamine and enhancing the dopaminergic activity in the substantial nigra. Selegiline may also increase dopaminergic activity through mechanisms other than inhibition of MAO-B. At higher doses, selegiline can also inhibit monozmine oxidase type A (MAO-A), allowing it to be used for the treatment of depression. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapidly absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): > 99.5% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 1.2-2 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD 50 =63 mg/kg (rats, IV) •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Emsam, Zelapar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (−)-selegiline L-Deprenalin (common) Selegilina (common) Selegiline (common) Selegilinum (common)

Do Abaloparatide and Selexipag interact?

•Drug A: Abaloparatide •Drug B: Selexipag •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Selexipag. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •References: 1. Lee CH, Strosberg AM, Carver LA: Antihypertensive drugs: their postural hypotensive effect and their blood pressure lowering activity in conscious normotensive rats. Arch Int Pharmacodyn Ther. 1983 Jan;261(1):90-101. [https://go.drugbank.com/articles/A177104] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Selexipag is indicated for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce risk of hospitalization. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): At the maximum tolerated dose of 1600 mcg twice per day, selexipag was not found to prolong the QT interval to a clinically relevant extent. Both selexipag and its metabolite caused concentration-dependent inhibition of platelet aggregation in vitro with IC50 of 5.5 µM and 0.21 µM, respectively. However, at clinically relevant concentrations, there was no effect on platelet aggregation test parameters following multiple dose administration of selexipag in healthy patients. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Selexipag is a selective prostacyclin (IP, also called PGI2) receptor agonist. The key features of pulmonary arterial hypertension include a decrease in prostacyclin and prostacyclin synthase (enzyme that helps produce prostacyclin) in the lung. Prostacyclin is a potent vasodilator with anti-proliferative, anti-inflammatory, and anti-thrombotic effects; therefore, there is strong rationale for treatment with IP receptor agonists. Selexipag is chemically distinct as it is not PGI2 or a PGI2 analogue and has high selectivity for the IP receptor. It is metabolized by carboxylesterase 1 to yield an active metabolite (ACT-333679) that is approximately 37 times more potent than selexipag. Both selexipag and its metabolite are selective for the IP receptor over other prostanoid receptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): After oral administration, maximum concentrations of selexipag and its metabolite were observed to be reached at 1-3 and 3-4 hours, respectively. Absorption was impaired in the presence of food, resulting in delayed time to maximum concentration as well as ~30% lower peak plasma concentration. However, exposure was not found to be significantly affected by food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Both selexipag and its active metabolite are highly protein bound, approximately 99%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Selexipag yields its active metabolite by hydrolysis of the acylsulfonamide by the enzyme hepatic carboxylesterase 1. Oxidative metabolism catalyzed by CYP3A4 and CYP2C8 results in hydroxylated and dealkylated products. UGT1A3 and UGT2B7 are involved in the glucuronidation of the active metabolite. Other than active metabolite, other metabolites in circulation do not exceed 3% of the total drug-related material. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 93% in feces, 12% in urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Selexipag's terminal half life is 0.8-2.5 hours. The active metabolite's terminal half life is 6.2-13.5 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): On average, 35 L/hour. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): A 40-70% increase in exposure was observed in subjects with severe renal impairment. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Uptravi, Uptravi Titration Pack •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Sevoflurane interact?

•Drug A: Abaloparatide •Drug B: Sevoflurane •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Sevoflurane is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Sevoflurane is used for the induction and maintenance of general anesthesia in adult and pediatric patients for inpatient and outpatient surgery. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Sevoflurane induces muscle relaxation and reduces sensitivity by altering tissue excitability with a fast onset of action. It does so by decreasing the extent of gap junction-mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. Compared to halothane and isoflurane, sevoflurane has a shorter emergence time, as well as a shorter time to first analgesia. To reach an equilibrium between alveolar and arterial partial pressure, only a minimal amount of sevoflurane needs to be dissolved in blood. The use of sevoflurane can increase the risk of renal injury, respiratory depression, and QT prolongation. Also, it can lead to malignant hyperthermia, perioperative hyperkalemia, and pediatric neurotoxicity. Episodes of severe bradycardia and cardiac arrest have been reported in pediatric patients with Down Syndrome given sevoflurane. Sevoflurane anesthesia may impair the performance of activities requiring mental alertness, such as driving or operating machinery. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The precise mechanism of action of sevoflurane has not been fully elucidated. Like other halogenated inhalational anesthetics, sevoflurane induces anesthesia by binding to ligand-gated ion channels and blocking CNS neurotransmission. It has been suggested that inhaled anesthetics enhance inhibitory postsynaptic channel activity by binding GABA A and glycine receptors, and inhibit excitatory synaptic channel activity by binding nicotinic acetylcholine, serotonin, and glutamate receptors. Sevoflurane has an effect on several ionic currents, including the hyperpolarisation-activated cation current (I f ), the T-type and L-type Ca currents (I Ca, T and I Ca, L ), the slowly activating delayed rectifier K currents (I Ks ), and the Na /Ca exchange current (I NCX ). This ability to modulate ion channel activity can also regulate cardiac excitability and contractility. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Sevoflurane is rapidly absorbed into circulation through the lungs; however, solubility in the blood is low (blood/gas partition coefficient at 37°C ranges from 0.63 to 0.69). Therefore, a minimal amount of sevoflurane needs to be dissolved in blood in order to induce anesthesia. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Patients given low-flow sevoflurane anesthesia during maxillofacial surgery (n=16) had a peripheral volume of distribution of 1634 ml vapour /kg bw and a total volume of distribution of 1748 ml vapour /kg bw. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Sevoflurane protein binding has not been evaluated. In vitro analyses have shown that other fluorinated volatile anesthetics can displace drugs from serum and tissue proteins; however, it is unclear if this is clinically significant. Clinical studies have shown that the administration of sevoflurane does not have a significant effect in patients taking drugs that are highly bound and have a small volume of distribution. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Sevoflurane is metabolized to hexafluoroisopropanol by cytochrome P450 2E1 in a reaction that promotes the release of inorganic fluoride and carbon dioxide. Hexafluoroisopropanol is rapidly conjugated with glucuronic acid and eliminated in urine. In vivo metabolism studies suggest that approximately 5% of the sevoflurane dose may be metabolized. In most cases, inorganic fluoride reaches its highest concentration within 2 hours of the end of sevoflurane anesthesia, and returns to baseline levels within 48 hours. Sevoflurane metabolism may be induced by chronic exposure to isoniazid and ethanol, and it has been shown that barbiturates do not affect it. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The low solubility of sevoflurane facilitates its rapid elimination through the lungs, where 95% to 98% of this anesthetic is eliminated. Up to 3.5% of the sevoflurane dose appears in urine as inorganic fluoride, and as much as 50% of fluoride clearance is nonrenal (fluoride taken up into bone). •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half-life of sevoflurane from the peripheral fat compartment is approximately 20 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): In patients given low-flow sevoflurane anaesthesia during maxillofacial surgery (n=16), the transport clearance from the central to the peripheral compartment was 13.0 ml vapour /kg bw ⋅min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): In the event of sevoflurane overdosage (or what may appear to be overdosage) discontinue administration, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. Patients experiencing an overdose may be at an increased risk of severe adverse effects such as renal injury, respiratory depression, severe bradycardia and cardiac arrest. Fatalities due to sevoflurane abuse have been reported as well. Symptomatic and supportive measures are recommended. Animal studies have shown that the use of anesthetic agents during periods of rapid brain growth or synaptogenesis results in alterations in synaptic morphology and neurogenesis. In primates, anesthetic regimens of up to 3 hours did not increase neuronal cell loss, but regimens of 5 hours or longer did have a significant effect. The oral LD 50 of sevoflurane is 10.8 g/kg in rats and 18.2 g/kg in mice. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Sevorane, Sojourn, Ultane •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1,1,1,3,3,3-Hexafluoro-2-(fluoromethoxy)propane Sevofluran (common) Sevoflurane (common) Sevoflurano (common) Sevofluranum (common)

Do Abaloparatide and Sildenafil interact?

•Drug A: Abaloparatide •Drug B: Sildenafil •Severity: MINOR •Description: The risk or severity of hypotension can be increased when Sildenafil is combined with Abaloparatide. •Extended Description: The subject drug is a phosphodiesterase 5 inhibitor which can lower blood pressure.1 The affected drug can cause hypotension, particularly orthostatic hypotension. Concomitant administration of these medications may lead to an increased risk of hypotension and orthostatic hypotension. •References: 1. Schwartz BG, Kloner RA: Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation. 2010 Jul 6;122(1):88-95. doi: 10.1161/CIRCULATIONAHA.110.944603. [https://go.drugbank.com/articles/A33630] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor that is predominantly employed for two primary indications: (1) the treatment of erectile dysfunction; and (2) treatment of pulmonary hypertension, where: a) the US FDA specifically indicates sildenafil for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil was added to background epoprostenol therapy. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%); b) the Canadian product monograph specifically indicates sildenafil for the treatment of primary pulmonary arterial hypertension (PPH) or pulmonary hypertension secondary to connective tissue disease (CTD) in adult patients with WHO functional class II or III who have not responded to conventional therapy. In addition, improvement in exercise ability and delay in clinical worsening was demonstrated in adult patients who were already stabilized on background epoprostenol therapy; and c) the EMA product information specifically indicates sildenafil for the treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease. The EMA label also indicates sildenafil for the treatment of pediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary hemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): In vitro studies have shown that sildenafil is selective for phosphodiesterase-5 (PDE5). Its effect is more potent on PDE5 than on other known phosphodiesterases. In particular, there is a 10-times selectivity over PDE6 which is involved in the phototransduction pathway in the retina. There is an 80-times selectivity over PDE1, and over 700-times over PDE 2, 3, 4, 7, 8, 9, 10 and 11. And finally, sildenafil has greater than 4,000-times selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility. In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (via the use of RigiScan®), after sildenafil administration compared with placebo. Most studies assessed the efficacy of sildenafil approximately 60 minutes post-dose. The erectile response, as assessed by RigiScan®, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours. Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. After chronic dosing of 80 mg, three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mmHg respectively. After chronic dosing of 80 mg, three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg). At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported either. In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output and did not impair blood flow through the stenosed coronary arteries. Mild and transient differences in color discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in color discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (which included visual acuity, Amsler grid, color discrimination simulated traffic light, and the Humphrey perimeter and photostress test). •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Sildenafil is an oral therapy for erectile dysfunction. In the natural setting, i.e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis. The physiological mechanism responsible for the erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects. Moreover, apart from the presence of PDE5 in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Sildenafil is known to be quickly absorbed, with maximum plasma concentrations being observed within 30-120 minutes (with a median of 60 minutes) of oral administration in a fasting patient. Moreover, the mean absolute bioavailability observed for sildenafil is about 41% (from a range of 25-63%). In particular, after oral three times a day dosing of sildenafil, the AUC and Cmax increase in proportion with dose over the recommended dosage range of 25-100 mg. When used in pulmonary arterial hypertension patients, however, the oral bioavailability of sildenafil after a dosing regimen of 80 mg three times a day, was on average 43% greater than compared to the lower doses. Finally, if sildenafil is administered orally with food, the rate of absorption is observed to be decreased with a mean delay in Tmax of about 60 minutes and a mean decrease in Cmax of approximately 29%. Regardless, the extent of absorption is not observed to be significantly affected as the recorded AUC decreased by only about 11 %. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The mean steady-state volume of distribution documented for sildenafil is approximately 105 L - a value which suggests the medication undergoes distribution into the tissues. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): It is generally observed that sildenafil and its main circulating N-desmethyl metabolite are both estimated to be about 96% bound to plasma proteins. Nevertheless, it has been determined that protein binding for sildenafil is independent of total drug concentrations. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The metabolism of sildenafil is facilitated primarily by the CYP3A4 hepatic microsomal isoenzymes and to a minor extent, via the CYP2C9 hepatic isoenzymes. The predominant circulating metabolite results from the N-demethylation of sildenafil. This particular resultant metabolite possesses a phosphodiesterase selectivity that is similar to the parent sildenafil molecule and a corresponding in vitro potency for PDE5 that is approximately 50% that of the parent drug. Moreover, plasma concentrations of the metabolite are about 40% of those recorded for sildenafil, a percentage that accounts for about 20% of sildenafil’s pharmacologic effects. This primary N-desmethyl metabolite of sildenafil also undergoes further metabolism, with a terminal half-life of about 4 hours. In patients with pulmonary arterial hypertension, plasma concentrations of the primary N-desmethyl metabolite are about 72% those of the original parent sildenafil molecule after a regimen of 20 mg three times a day - which is consequently responsible for about a 36% contribution to sildenafil’s overall pharmacological effects. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal phase half-life observed for sildenafil is approximately 3 to 5 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The total body clearance documented for sildenafil is 41 L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): In single-dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased. Doses of 200 mg did not result in increased efficacy but the incidence of adverse reaction (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was increased. Due to the lack of data on the effect of sildenafil indicated for the treatment of pulmonary arterial hypertension (PAH) in pregnant women, sildenafil is not recommended for women of childbearing potential unless also using appropriate contraceptive measures. The safety and efficacy of sildenafil indicated for treating PAH in a woman during labor and delivery have not been studied. Caution should ultimately be exercised when sildenafil is administered to nursing women as it is not known if sildenafil or its metabolites are excreted in human breast milk. The safety and efficacy of sildenafil for the treatment of PAH in children below 1 year of age has not been established as no data is available. Clinical experience with the elderly population in the use of sildenafil for the treatment of PAH has been varied. Some reports suggest that there are no identified differences in responses between elderly and younger patients while others have documented that clinical efficacy as measured by 6-minute walk distance could be less in elderly patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Conversely, when sildenafil was used to treat erectile dysfunction in healthy elderly volunteers (65 years or over), a reduced clearance of sildenafil was observed. This reduction resulted in about 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%. Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 29- and 42- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/m2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Liqrev, Revatio, Viagra, Vizarsin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-((3-(4,7-Dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo(4,3-d)pyrimidin-5-yl)-4-ethoxyphenyl)sulfonyl)-4-methylpiperazine Sildenafil (common) Sildenafilo (common)

Do Abaloparatide and Sodium ferric gluconate complex interact?

•Drug A: Abaloparatide •Drug B: Sodium ferric gluconate complex •Severity: MODERATE •Description: The risk or severity of hypotension can be increased when Sodium ferric gluconate complex is combined with Abaloparatide. •Extended Description: Ferrlecit may cause clinically significant hypotension.1 Hypotension associated with lightheadedness, malaise, fatigue, weakness or severe pain in the chest, back, flanks, or groin has been reported. These hypotensive reactions may or may not be associated with signs and symptoms of hypersensitivity reactions and usually resolve within one to two hours. Therefore, concomitant use of sodium ferric gluconate complex with hypotensive agents can exacerbate its hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Sodium ferric gluconate complex in sucrose injection is used to deplete the total body content of iron during iron deficiency anemia in patients aged 6 years and older with chronic kidney disease receiving hemodialysis and receiving supplemental epoetin therapy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Sodium ferric gluconate complex is an exogenous epoetin that acts to restore the body's content of iron, which is essential for normal hemoglobin synthesis, oxygen transport, and enzymatic processes. The complex increases red blood cell production and increased iron utilization. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The complex is endocytosed by macrophages of the reticuloendothelial system. Within an endosome of the macrophage, lysosome fuses with the endosome creating an acidic environment leading to the cleavage of the complex from iron. Iron is then incorporated in ferritin, transferrin or hemoglobin. Sodium ferric gluconate also normalizes RBC production by binding with hemoglobin •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Peak drug levels (Cmax) varied significantly by dosage and by rate of administration. Highest Cmax value is observed in the regimen in which 125 mg was administered in 7 minutes (19.0 mg/L). •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Using single-dose pharmacokinetics of either 1.5 or 3 mg/kg in pediatric patients (mean age 12.3 ± 2.5 yr), the volume of distribution was estimated to be 1.6 ± 0.6 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): It is bound to transferrin, ferritin and hemoglobin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): It is renally eliminated if it is greater than 18,000 Daltons. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half-life for drug-bound iron was approximately 1 hour, with the value varying by dose but not by rate of administration. In adults, the shortest terminal elimination half-life of 0.825h occurs with the 62.5 mg/4 min dosing regimen and the longest value of 1.45h is achieved with 125 mg/7 min regimen. In pediatric patients, the half-life was 2 hours following administration of 1.5 mg/kg dose and 2.5 hours following administration of 3.0mg/kg dose. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total clearance ranges from 3.02 to 5.35 L/h in adult patients. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The Ferrlecit iron complex is not dialyzable. No data is available regarding overdose of Ferrlecit in humans. Excessive dosages of Ferrlecit may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. Do not administer Ferrlecit to patients with iron overload [see Warnings and Precautions (5.3)]. Individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events [see Adverse Reactions (6.2)]. Ferrlecit at elemental iron doses of 125 mg/kg, 78.8 mg/kg, 62.5 mg/kg, and 250 mg/kg caused deaths in mice, rats, rabbits, and dogs respectively. The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in respiratory rate, tremors, and convulsions. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Ferrlecit •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Sotalol interact?

•Drug A: Abaloparatide •Drug B: Sotalol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Sotalol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Sotalol is indicated to treat life threatening ventricular arrhytmias and maintain normal sinus rhythm in patients with atrial fibrillation or flutter. There are also oral solutions and intravenous injections indicated for patients requiring sotalol, but for whom a tablet would not be appropriate. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Sotalol is a competitive inhibitor of the rapid potassium channel. This inhibition lengthens the duration of action potentials and the refractory period in the atria and ventricles. The inhibition of rapid potassium channels is increases as heart rate decreases, which is why adverse effects like torsades de points is more likely to be seen at lower heart rates. L-sotalol also has beta adrenergic receptor blocking activity seen above plasma concentrations of 800ng/L. The beta blocking ability of sotalol further prolongs action potentials. D-sotalol does not have beta blocking activity but also reduces a patient's heart rate while standing or exercising. These actions combine to produce a negative inotropic effect that reduces the strength of contractility of muscle cells in the heart. Extension of the QT interval is also adversely associated with the induction of arrhythmia in patients. Hyperglycemia is a greater risk for non insulin dependant diabetics than insulin dependant diabetics. Beta blockers inhibit insulin secretion which may cause hyperglycemia in type II diabetes mellitus. The risk of hypoglycemia is higher in insulin dependant diabetes than non insulin dependant diabetics. Beta blockers decrease secretion of insulin, which may mask hypoglycemia in an insulin dependant patient. Beta blockers also increase glucose uptake into cells which may prolong or potentiate hypoglycemia. Further information regarding adverse reactions can be found here. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Sotalol inhibits beta-1 adrenoceptors in the myocardium as well as rapid potassium channels to slow repolarization, lengthen the QT interval, and slow and shorten conduction of action potentials through the atria. The action of sotalol on beta adrenergic receptors lengthens the sinus node cycle, conduction time through the atrioventricular node, refractory period, and duration of action potentials. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Sotalol is 90-100% bioavailable. When taken with a meal, adsorption is lowered by 18%. In patients with a creatinine clearance >80mL/min, the maximum concentration is 6.25±2.19. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution is 1.2-2.4L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 0%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Sotalol is not metabolized. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 80-90% of a given dose is excreted in the urine as unchanged sotalol. A small fraction of the doses is excreted in the feces as unchanged sotalol. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half life is 10-20 hours in healthy patients. In patients with a creatinine clearance >80mL/min, the half life is 17.5±0.97h. In patients with a creatinine clearance 30-80mL/min, the half life is 22.7±6.4h. In patients with a creatinine clearance 10-30mL/min, the half life is 64±27.2h. In patients with a creatinine clearance <10mL/min, the half life is 97.9±57.3h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): In patients with a creatinine clearance >80mL/min, the plasma clearance is 6.78±2.72L/h and the renal clearance is 4.99±1.43L/h. In patients with a creatinine clearance 30-80mL/min, the plasma clearance is 2.74±0.53L/h and the renal clearance is 2.00±0.67L/h. In patients with a creatinine clearance 10-30mL/min, the plasma clearance is 1.56±0.44L/h and the renal clearance is 0.65±0.31L/h. In patients with a creatinine clearance <10mL/min, the plasma clearance is 0.65±0.20L/h and the renal clearance is 0.27±0.13L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Patients experiencing an overdose may present with bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia. Larger intentional overdoses may present as hypotension, bradycardia, cardiac asystole, prolonged QT interval, torsade de pointes, ventricular tachycardia, and premature ventricular complexes. Stop administering sotalol and observe the patient until the QT interval returns to normal and the heart rate rises above 50 beats per minute. Hemodialysis may help lower plasma concentrations of sotalol as it is not bound to plasma proteins. Bradycardia and cardiac asystole may be treated with atropine, other anticholinergic drugs, beta adrenergic agonists, or transvenous cardiac pacing.. Second or third degree heart block may be treated with a transvenous cardiac pacemaker. Hypotension may be treated with epinephrine or norepinephrine. Bronchospasm may be treated with aminophylline or a beta-2 agonist, possibly at higher than normal doses. Torsade de pointes may be treated with DC cardioversion, transvenous cardiac pacing, epinephrine, or magnesium sulfate. The oral LD50 for rats is 3450mg/kg, intraperitoneal LD50 for rats is 680mg/kg, oral LD50 for mice is 2600mg/kg, and intraperitoneal LD50 for mice is 670mg/kg. Pregnant rabbits given 6 times the maximum recommended human dose showed an increase in fetal death and maternal toxicity, while rats given 18 times the maximum recommended human dose had an increased number of fetal resorptions. Sotalol is present in human breast milk so patients taking sotalol should not breast feed. Sotalol has not been found to be carcinogenic. No studies have been performed regarding mutagenicity or clastogenicity. In animal studies, sotalol was not associated with a reduction in fertility aside from smaller litter sizes. Further information regarding adverse reactions can be found here. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Betapace, Sorine, Sotylize •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 4'-(1-hydroxy-2-(isopropylamino)ethyl)methane sulfonanilide Sotalol (common) Sotalolo (common) Sotalolum (common) β-cardone

Do Abaloparatide and Spironolactone interact?

•Drug A: Abaloparatide •Drug B: Spironolactone •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Spironolactone is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Spironolactone is indicated for the treatment of the following conditions: NYHA Class III-IV heart failure and reduced ejection fraction to increase survival, manage edema, and reduce the need for hospitalization for heart failure. Spironolactone is usually administered in conjunction with other heart failure therapies. Hypertension, as add-on therapy, in patients not adequately controlled by other agents. Edema associated with hepatic cirrhosis when edema is not responsive to fluid and sodium restriction. Edema associated with nephrotic syndrome when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics produce an inadequate response. Refractory edema associated with congestive cardiac failure, malignant ascites, hepatic cirrhosis with ascites, and essential hypertension. Short-term preoperative treatment of patients with primary hyperaldosteronism. Diagnosis of primary aldosteronism. Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are not candidates for surgery. Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism). As spironolactone has antiandrogenic activity, its off-label uses include the treatment of hirsutism, female pattern hair loss, and adult acne vulgaris. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Spironolactone has a potassium-sparing diuretic effect. It promotes sodium and water excretion and potassium retention. It increases renin and aldosterone levels. Spironolactone is a mineralocorticoid receptor antagonist and has a low affinity for the glucocorticoid receptor. It also exhibits progestogenic and anti-androgenic actions as it binds to the androgen receptor and, to a lesser extent, estrogen and progesterone receptors. Spironolactone exhibits anti-inflammatory effects. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Aldosterone is a key hormone in the renin-angiotensin-aldosterone system. By binding to the mineralocorticoid receptor at the distal tubules and collecting duct, it causes sodium reabsorption and potassium secretion, increases vascular stiffness and remodelling, and activates pro-inflammatory pathways. Spironolactone and its active metabolites are aldosterone antagonists that produce a potassium-sparing diuretic effect. They competitively bind to receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents that act more proximally in the renal tubule. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The mean time to reach peak plasma concentration of spironolactone and the active metabolite, canrenone, in healthy volunteers is 2.6 and 4.3 hours, respectively. Food increased the bioavailability of spironolactone (as measured by AUC) by approximately 95.4%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Spironolactone and its metabolites are more than 90% bound to plasma proteins. Spironolactone and canrenone bind to serum albumin and alpha 1-acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Spironolactone is rapidly and extensively metabolized to form different metabolites. A group of metabolites are formed when sulfur of spironolactone is removed, such as canrenone. Sulfur is retained in another group of metabolites, including 7-alpha (α)-thiomethylspironolactone (TMS) and 6-beta (ß)-hydroxy-7-alpha (α)-thiomethylspirolactone (HTMS). Spironolactone is firstly deacetylated to 7-α-thiospironolactone. 7-α-thiospironolactone is S-methylated to TMS, which is the primary metabolite, or dethioacetylated to canrenone. TMS and HTMS can be further metabolized. In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were approximately a third relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The metabolites are excreted primarily in the urine and secondarily in bile. Metabolites of spironolactone are excreted in urine (42-56%) and in the feces (14.2-14.6%). No unmetabolized spironolactone is present in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean half-life of spironolactone is 1.4 hours. The mean half-life values of its metabolites, including canrenone, TMS, and HTMS are 16.5, 13.8, and 15 hours, respectively. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 of spironolactone is greater than 1000 mg/kg in mice, rats, and rabbits. Acute overdosage of ALDACTONE may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia,or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. Hyperkalemia may occur, especially in patients with impaired renal function. In case of an overdose, vomiting may be induced and gastric lavage may be instituted. As there is no specific antidote, treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Patients who have renal impairment may develop hyperkalemia. In such cases, discontinue spironolactone. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Aldactazide, Aldactone, Carospir •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Streptokinase interact?

•Drug A: Abaloparatide •Drug B: Streptokinase •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Streptokinase is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of acute evolving transmural myocardial infarction, pulmonary embolism, deep vein thrombosis, arterial thrombosis or emolism and occlusion of arteriovenous cannulae •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Streptokinase creates an active complex which promotes the cleavage of the Arg/Val bond in plasminogen to form the proteolytic enzyme plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. This helps eliminate blood clots or arterial blockages that cause myocardial infarction. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Plasminogen is an inactive molecule that becomes activated to plasmin when the Arg/Val bond is cleaved. Plasmin breaks down fibrin clots created by the blood clotting cascade. Streptokinase forms a highly specific 1:1 enzymatic complex with plasminogen which converts inactive plasminogen molecules into active plasmin. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins. This in turn leads to the degradation of blood clots. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Sufentanil interact?

•Drug A: Abaloparatide •Drug B: Sufentanil •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Sufentanil is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): The indications for this drug are as follows: As an analgesic adjunct in the maintenance of balanced general anesthesia in patients who are intubated and ventilated. As a primary anesthetic agent for the induction and maintenance of anesthesia with 100% oxygen in patients undergoing major surgical procedures, in patients who are intubated and ventilated, such as cardiovascular surgery or neurosurgical procedures in the sitting position, to provide favorable myocardial and cerebral oxygen balance or when extended postoperative ventilation is anticipated. For epidural administration as an analgesic combined with low dose (usually 12.5 mg per administration) bupivacaine usually during labor and vaginal delivery The sublingual form is indicated for the management of acute pain in adults that is severe to warrant the use of an opioid analgesic in certified medically supervised healthcare settings, including hospitals, surgical centers, and emergency departments. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Effect on the Central Nervous System (CNS) In clinical settings, sufentanil exerts its principal pharmacologic effects on the central nervous system. Its primary therapeutic actions are analgesia and sedation. Sufentanil may increase pain tolerance and decrease the perception of pain. This drug depresses the respiratory centers, depresses the cough reflex, and constricts the pupils,. When used in balanced general anesthesia, sufentanil has been reported to be as much as 10 times as potent as fentanyl. When administered intravenously as a primary anesthetic agent with 100% oxygen, sufentanil is approximately 5 to 7 times as potent as fentanyl. High doses of intravenous sufentanil have been shown to cause muscle rigidity, likely as a result of an effect on the substantia nigra and the striate nucleus in the brain. Sleep-inducing (hypnotic) activity can be demonstrated by EEG alterations. Effects on the Respiratory System Sufentanil may cause respiratory depression. Effects on the Cardiovascular System Sufentanil causes peripheral vasodilation which may result in orthostatic hypotension or syncope. Bradycardia may also occur. Clinical signs or symptoms of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Gastrointestinal Tract Sufentanil causes a reduction in motility associated with an increase in smooth muscle tone in both the antrum of the stomach and duodenum. Digestion of food in the small intestine may be delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased and lead to spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of the sphincter of Oddi, as well as temporary elevations in serum amylase. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Sufentanil is a synthetic, potent opioid with highly selective binding to μ-opioid receptors. These receptors are widely distributed in the human brain, spinal cord, and other tissues,. In general, opioids decrease cAMP (affecting neural signaling pathways), decrease neurotransmitter release, and cause membrane hyperpolarization, all of which contribute to the relief of painful symptoms. Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic neural transmission via G-proteins that activate effector proteins. Binding of the opiate receptor leads to the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP, located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. The release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine, and noradrenaline is then inhibited. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist), also preventing neurotransmitter release. Sufentanil and other opioids open calcium-dependent inwardly rectifying potassium channels, resulting in hyperpolarization and reduced neuronal excitability,. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bioavailability of a single sublingual tablet was 52%, decreasing to 35% with repeat dosing. After epidural administration of incremental doses totaling 5 to 40 mcg sufentanil during labor and delivery, maternal and neonatal sufentanil plasma concentrations were at or near the 0.05 to 0.1 ng/mL limit of detection, and were slightly higher in mothers than in their infants. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Sufentanil has a distribution time of 1.4 minutes and redistribution time of 17.1 minutes. The central volume of distribution after intravenous application of sufentanil is approximately 14 L and the volume of distribution at steady state is approximately 350 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Plasma protein binding of sufentanil, related to the alpha acid glycoprotein concentration, was approximately 93% in healthy males, 91% in mothers and 79% in neonates. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The liver and small intestine are the major sites of biotransformation. Sufentanil is rapidly metabolized to a number of inactive metabolites, with oxidative N- and O-dealkylation being the major routes of elimination. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half-life is 164 minutes in adults when administered intravenously (IV). The elimination half-life of sufentanil is shorter (e.g. 97 +/- 42 minutes) in infants and children, and longer in neonates (e.g. 434 +/- 160 minutes) compared to that of adolescents and adults. After a single administration of a 15 microgram sufentanil sublingual tablet, mean terminal phase half-lives in the range of 6-10 hours have been observed. After multiple administrations, a longer average terminal half-life of up to 18 hours was measured, owing to the higher plasma concentrations of sufentanil achieved after repeated dosing and due to the possibility to quantify these concentrations over a longer time period. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The total plasma clearance after single intravenous administration is about 917 l/min. The clearance of sufentanil in healthy neonates is approximately one-half that in adults and children. The clearance rate of sufentanil can be further reduced by up to a third in neonates with cardiovascular disease. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD 50: 18.7 mg/kg (IV in mice) A Note on Respiratory Depression Major, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even in cases where it is used as recommended. Respiratory depression may lead to respiratory arrest and death if not diagnosed and treated appropriately. This drug should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiration and cardiac resuscitation of patients in the age group being treated. This training must include the establishment and maintenance of a patent airway and assisted ventilation. Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of sufentanil have not been conducted. Mutagenesis Sufentanil was not found to be genotoxic in the in vitro bacterial reverse mutation assay (Ames assay) or in the in vivo rat bone marrow micronucleous assay. Reproductive Toxicity Sufentanil caused embryolethality in rats and rabbits treated for 10-30 days during pregnancy with 2.5 times the maximum human dose by intravenous administration. The embryolethal effect was thought to be secondary to the toxicity for the mother animal model. No negative effects were noted in another study in rats that were treated with 20 times the maximum human dose in the period of organogenesis. The preclinical effects were only seen following administrations of levels significantly above the maximum human dose, which is therefore of minimal relevance for clinical use. Pregnancy May cause fetal harm The Use in Lactation Infants exposed to this drug through breast milk should be monitored for excess sedation and respiratory depression. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Dsuvia, Sufenta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): N-(4-(Methoxymethyl)-1-(2-(2-thienyl)ethyl)-4-piperidinyl)-N-phenylpropanamide N-(4-(Methoxymethyl)-1-(2-(2-thienyl)ethyl)-4-piperidyl)propionanilide Sufentanil (common) Sufentanilo (common) Sufentanilum (common) Sufentanyl (common)

Do Abaloparatide and Tadalafil interact?

•Drug A: Abaloparatide •Drug B: Tadalafil •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Tadalafil. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •References: 1. Lee CH, Strosberg AM, Carver LA: Antihypertensive drugs: their postural hypotensive effect and their blood pressure lowering activity in conscious normotensive rats. Arch Int Pharmacodyn Ther. 1983 Jan;261(1):90-101. [https://go.drugbank.com/articles/A177104] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Tadalafil is indicated for the treatment of erectile dysfunction (ED) and either alone or in combination with finasteride for the treatment of benign prostatic hypertrophy (BPH). It is also indicated for the treatment of pulmonary arterial hypertension (PAH) both alone and in combination with macitentan or other endothelin-1 antagonists. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Tadalafil exerts a therapeutic effect in ED by increasing sexual stimulation-dependant smooth muscle relaxation in the penis, allowing the corpus cavernosum to fill with blood to produce an erection. Smooth muscle relaxation in the pulmonary vasculature helps to produce vasodilation in PAH which reduces blood pressure in the pulmonary arteries. In BPH, tadalafil may contribute to decreased smooth muscle cell proliferation which may reduce the size of the prostate and relieve the anatomical obstruction which produces urinary symptoms of BPH. The decreased affinity of tadalafil for PDE6 compared to other PDE5 inhibitors may explain the reduced incidence of visual side effects. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Tadalafil is a selective phosphodiesterase-5 (PDE5) inhibitor that produces several downstream effects with the most common therapeutic effect being smooth muscle relaxation. Patients may experience ED due to a variety of causes including psychogenic, neurogenic, vasculogenic, iatrogenic, or endocrine. These causes result in dysfunction of penile smooth muscle relaxation through either disrupted neuronal signaling or direct influence on smooth muscle cells. During sexual arousal, non-adrenergic non-cholinergic (NANC) neurons release nitric oxide (NO). Nitric oxide stimulates guanylate cyclase which converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP). cGMP activates the cGMP-dependent kinase (PKG) in a signal cascade which activates K+ channels leading to inhibition of Ca2+ channels, inhibits platelet activation, and inhibits smooth muscle cell proliferation while inducing apoptosis. This signal cascade is attenuated by PDE5 which breaks the phosphodiester bond of cGMP, converting it to GMP. Inhibition of PDE5 by tadalafil increases signaling via the PKG cascade which supports penile smooth muscle relaxation during sexual arousal by decreasing Ca2+ entry into smooth muscle cells. This smooth muscle relaxation allows blood to fill the corpus cavernosum thereby producing an erection. In PAH, blood pressure in the pulmonary arteries is raised due to a variety of mechanisms stemming from endothelial dysfunction. Decreased production of NO and prostacyclin reduce vasodilatory signaling while overproduction of endothelin-1 and thromboxane increase vasoconstriction. Inflammation, thromboses, and hypoxia later contribute to vascular remodeling which further reduces luminal size. The resultant increase in blood pressure reduces the capacity for gas exchange and increases afterload at the right ventricle, producing symptoms of dyspnea, fatigue, and dizziness as well as leading to right-sided heart failure. Tadalafil exerts its therapeutic effect in PAH through boosting NO-cGMP signaling to contribute to smooth muscle relaxation as with ED. Lastly, tadalafil is used to treat BPH. BPH produces urinary dysfunction through hyperproliferation of the epithelial and smooth muscle layers of the prostate. The increased size of the prostate blocks urine flow through the urethra resulting in higher residual volumes due to incomplete emptying. Tadalafil does not appear to exert its benefit via smooth muscle relaxation of the prostate. It may instead exert its effect through a mix of increased oxygenation and decreased inflammation, which decreases tissue remodeling, and inhibition of cell proliferation through the cGMP cascade. The decreased affinity for PDE6 compared to other PDE5 inhibitors may explain the decreased incidence of visual side effects as PDE6 is present in the eye and contributes to color vision. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Tadalafil has a tmax of 0.5-6h with a median of 2h in healthy adults. The tmax in adults with PAH is reported as 2-8h with a median of 4h. There does not appear to be a significant effect on absorption when tadalafil is taken with food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Tadalafil has a mean apparent volume of distribution of 63L in healthy adults. The mean apparent volume of distribution is reported as 77L in adults with PAH. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Tadalafil is 94% bound to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Tadalafil undergoes hepatic metabolism via CYP3A4 to a catechol metabolite. This catechol metabolite undergoes subsequent methylation and glucuronidation with the methyl-glucuronide metabolite becoming the primary metabolite in circulation. None of the known metabolites are considered to be active. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Tadalafil is primarily eliminated via hepatic metabolism. These metabolites are mainly excreted in the feces (61%) and to a lesser extent in the urine (36%) •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean half-life of elimination of tadalafil is 15-17.5h in healthy adults. The mean half-life of elimination in adults with PAH is reported as 35h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The mean apparent oral clearance of tadalafil is 2.5-3.4L/h in healthy adults. The mean apparent oral clearance in adults with PAH is reported as 3.5L/h •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose are expected to be similar to typical adverse effects which may include headache, dyspepsia, back pain, myalgia, nasopharyngitis, and dizziness. Standard supportive care is recommended. Hemodialysis is not expected to contribute significantly to tadalafil clearance. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Adcirca, Alyq, Cialis, Entadfi, Tadliq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (6R-trans)-6-(1,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino(1',2':1,6)pyrido(3,4-b)indole-1,4-dione (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-(methylenedioxy)phenyl) pyrazino(1',2':1,6)pyrido(3,4-b)indole-1,4-dione Tadalafil (common) Tadalafilo (common)

Do Abaloparatide and Tamsulosin interact?

•Drug A: Abaloparatide •Drug B: Tamsulosin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Tamsulosin is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Tamsulosin is indicated for the treatment of signs and symptoms of benign prostatic hyperplasia. Tamsulosin is also used off label for the treatment of ureteral stones, prostatitis, and female voiding dysfunction. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Tamsulosin is an alpha adrenoceptor blocker with specificity for the alpha-1A and alpha-1D subtypes, which are more common in the prostate and submaxillary tissue. The final subtype, alpha-1B, are most common in the aorta and spleen. Tamsulosin binds to alpha-1A receptors 3.9-38 times more selectively than alpha-1B and 3-20 times more selectively than alpha-1D. This selectivity allows for a significant effect on urinary flow with a reduced incidence of adverse reactions like orthostatic hypotension. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Tamsulosin is a blocker of alpha-1A and alpha-1D adrenoceptors. About 70% of the alpha-1 adrenoceptors in the prostate are of the alpha-1A subtype. By blocking these adrenoceptors, smooth muscle in the prostate is relaxed and urinary flow is improved. The blocking of alpha-1D adrenoceptors relaxes the detrusor muscles of the bladder which prevents storage symptoms. The specificity of tamsulosin focuses the effects to the target area while minimizing effects in other areas. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Oral tamsulosin is 90% absorbed in fasted patients. The area under the curve is 151-199ng/mL*hr for a 0.4mg oral dose and 440-557ng/mL*hr for a 0.8mg oral dose. The maximum plasma concentration is 3.1-5.3ng/mL for a 0.4mg oral dose and 2.5-3.6ng/mL for a 0.8mg oral dose. Taking tamsulosin with food increases the time to maximum concentration from 4-5 hours to 6-7 hours but increases bioavailability by 30% and maximum plasma concentration by 40-70%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 16L after intravenous administration. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Tamsulosin is 94%-99% protein bound, mostly to alpha-1-acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Tamsulosin is mostly metabolized in the liver by cytochrome P450 (CYP) 3A4 and 2D6, with some metabolism by other CYPs. CYP3A4 is responsible for the deethylation of tamsulosin to the M-1 metabolite and the oxidative deamination to the AM-1 metabolite, while CYP2D6 is responsible for the hydroxylation of tamsulosin to the M-3 metabolite and the demethylation of tamsulosin to the M-4 metabolite. In addition, tamsulosin can be hydroxylated at a different position by an unknown enzyme to form the M-2 metabolite. The M-1, M-2, M-3, and M-4 metabolites can be glucuronidated, and the M-1 and M-3 metabolites can undergo sulfate conjugation to form other metabolites before excretion. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 97% of an orally administered does is recovered in studies, which 76% in the urine and 21% in the feces after 168 hours. 8.7% of the dose is excreted as unmetabolized tamsulosin. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half life in fasted patients is 14.9±3.9 hours. The elimination half life is 5-7 hours and the apparent half life is 9 to 13 hours in healthy subjects. In patients who require tamsulosin, the apparent half life is 14-15 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 2.88L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): In the event of overdose, patients may experience hypotension and should lie down in a supine position to maintain blood pressure and heart rate. If further measures are required intravenous fluids should be considered. If further progression is required, vasopressors may be used and renal function should be monitored. Dialysis is unlikely to assist in treating overdose because tamsulosin is extensively protein bound. The oral LD50 in rats is 650mg/kg. Tamsulosin is not indicated for use in women and no studies have been performed in pregnancy, though animal studies have not shown fetal harm. Tamsulosin is excreted in the milk of rats but there is no available data on what the effect of this tamsulosin exposure may be. Animal studies have shown male and female rat fertility is affected by tamsulosin due to impairment of ejaculation and fertilization. In men, tamsulosin is associated with abnormal ejaculation. Tamsulosin is not mutagenic but may be carcinogenic at levels above the maximum recommended human dose. Female rats experience a slight increase in the rates of mammary gland fibroadenomas and adenocarcinomas. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Flomax, Jalyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (−)-tamsulosin (R)-(−)-tamsulosin (R)-5-(2-((2-(2-ethoxyphenoxy)ethyl)amino)propyl)-2-methoxybenzenesulfonamide Tamsulosin (common) Tamsulosina (common) Tamsulosine (common) Tamsulosinum (common)

Do Abaloparatide and Telmisartan interact?

•Drug A: Abaloparatide •Drug B: Telmisartan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Telmisartan is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used alone or in combination with other classes of antihypertensives for the treatment of hypertension. Also used in the treatment of diabetic nephropathy in hypertensive patients with type 2 diabetes mellitus, as well as the treatment of congestive heart failure (only in patients who cannot tolerate ACE inhibitors). •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Telmisartan is an orally active nonpeptide angiotensin II antagonist that acts on the AT 1 receptor subtype. It has the highest affinity for the AT 1 receptor among commercially available ARBs and has minimal affinity for the AT 2 receptor. New studies suggest that telmisartan may also have PPARγ agonistic properties that could potentially confer beneficial metabolic effects, as PPARγ is a nuclear receptor that regulates specific gene transcription, and whose target genes are involved in the regulation of glucose and lipid metabolism, as well as anti-inflammatory responses. This observation is currently being explored in clinical trials. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan works by blocking the vasoconstrictor and aldosterone secretory effects of angiotensin II. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Telmisartan interferes with the binding of angiotensin II to the angiotensin II AT 1 -receptor by binding reversibly and selectively to the receptors in vascular smooth muscle and the adrenal gland. As angiotensin II is a vasoconstrictor, which also stimulates the synthesis and release of aldosterone, blockage of its effects results in decreases in systemic vascular resistance. Telmisartan does not inhibit the angiotensin converting enzyme, other hormone receptors, or ion channels. Studies also suggest that telmisartan is a partial agonist of PPARγ, which is an established target for antidiabetic drugs. This suggests that telmisartan can improve carbohydrate and lipid metabolism, as well as control insulin resistance without causing the side effects that are associated with full PPARγ activators. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Oral telmisartan follows nonlinear pharmacokinetics over the dose range of 20 mg to 160 mg. Both C max and AUC present greater than proportional increases at higher doses. With once-daily dosing, telmisartan has trough plasma concentrations of about 10% to 25% of peak plasma concentrations. The absolute bioavailability of telmisartan depends on the dosage. At 40 mg and 160 mg, the bioavailability was 42% and 58%, respectively. Food slightly decreases bioavailability. For instance, when the 40 mg dose is administered with food, a decrease of about 6% is seen, and with the 160 mg dose, there is a decrease of about 20%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Telmisartan has a volume of distribution of approximately 500 liters. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and alpha 1-acid glycoprotein. Binding is not dose-dependent. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Minimally metabolized by conjugation to form a pharmacologically inactive acyl-glucuronide, the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following either intravenous or oral administration of 14C-labeled telmisartan, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively). •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Telmisartan displays bi-exponential decay kinetics with a terminal elimination half-life of approximately 24 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Telmisartan has a total plasma clearance of >800 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Intravenous LD 50 in rats is 150-200 mg/kg in males and 200 to 250 mg/kg in females. Acute oral toxicity is low: no deaths and no changes occurred in rats or dogs at 2000 mg/kg, the highest dose tested. Limited data are available with regard to overdosage in humans. The most likely manifestations of overdosage with telmisartan would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Supportive treatment should be instituted if symptomatic hypotension occurs. Telmisartan is not removed by hemofiltration and is not dialyzable. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Actelsar Hct, Micardis, Micardis-hct, Pritor, Twynsta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 4'-((1,4'-dimethyl-2'-propyl(2,6'-bi-1H-benzimidazol)-1'-yl)methyl)-(1,1'-biphenyl)-2-carboxylic acid 4'-((4-methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl)methyl)-2-biphenylcarboxylic acid 4'-[(1,4'-dimethyl-2'propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid 4'-[(1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzimidazol-3'-yl)methyl]biphenyl-2-carboxylic acid Telmisartan (common)

Do Abaloparatide and Terazosin interact?

•Drug A: Abaloparatide •Drug B: Terazosin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Terazosin is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Terazosin is indicated for use in treating symptomatic benign prostatic hyperplasia and hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Terazosin is a quinazoline derivative alpha-1-selective adrenergic blocker. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Terazosin is selective for alpha-1-adrenoceptors but not their individual subtypes. Inhibition of these alpha-1-adrenoceptors results in relaxation of smooth muscle in blood vessels and the prostate, lowering blood pressure and improving urinary flow. Smooth muscle cells accounts for roughly 40% of the volume of the prostate and so their relaxation reduces pressure on the urethra. It has also been shown that catecholamines induce factors responsible for mitogenesis and alpha-1-adrenergic receptor blockers inhibit this effect. A final long term mechanism of terazosin and other alpha-1-adrenergic receptor blockers is the induction of apoptosis of prostate cells. Treatment with terazosin enhances the expression of transforming growth factor beta-1 (TGF-beta1), which upregulates p27kip1, and the caspase cascade. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Approximately 90%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 25L to 30L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 90-94%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The majority of terazosin is hepatically metabolized. The metabolites recovered include 6-O-demethyl terazosin, 7-O-methyl terazosin, a piperozine derivative, and a diamine derivative. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 10% of the oral dose is excreted unchanged in the urine and approximately 20% is excreted in the feces. 40% of the total dose is eliminated in urine and 60% of the total dose is eliminated in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Terazosin has a mean half life 12 hours though this can be as high as 14 hours in patients over 70 years and as low as 11.4 hours in patients 20 to 39 years old. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Plasma clearance is 80mL/min and renal clearance is 10mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): In the event of an overdose, patients may experience hypotension. Blood pressure and heart rate should be controlled by having the patient lie down or by treating with volume expanders or if necessary vasopressors. Patients should be monitored for renal function. Because terazosin is highly protein bound, dialysis is unlikely to provide benefit to overdosing patients. The oral LD50 in mice is 5500mg/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-((tetrahydro-2-furanyl)carbonyl)piperazine Terazosin (common) Terazosina (common) Térazosine (common) Terazosine (common) Terazosinum (common)

Do Abaloparatide and Thalidomide interact?

•Drug A: Abaloparatide •Drug B: Thalidomide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Thalidomide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Thalidomide is primarily used for the acute treatment and maintenance therapy to prevent and suppress the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Thalidomide, originally developed as a sedative, is an immunomodulatory and anti-inflammatory agent with a spectrum of activity that is not fully characterized. However, thalidomide is believed to exert its effect through inhibiting and modulating the level of various inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-a) and IL-6. Additionally, thalidomide is also shown to inhibit basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), suggesting a potential anti-angiogenic application of thalidomide in cancer patients. Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: the (+)R enantiomer is effective against morning sickness, and the (−)S enantiomer is teratogenic. The enantiomers are interconverted to each other in vivo; hence, administering only one enantiomer will not prevent the teratogenic effect in humans. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The mechanism of action of thalidomide is not fully understood. Previous research indicate that thalidomide binds to cerebron, a component of the E3 ubiquitin ligase complex, to selectively degrade the transcription factor IKZF3 and IKZF1. These 2 transcription factors are vital for the proliferation and survival of malignant myeloma cells. Regarding TNF-alpha, thalidomide seems to block this mediator via a variety of mechanism. Thalidomide can inhibit the expression myeloid differentiating factor 88 (MyD88), an adaptor protein that is involved in the TNF-alpha production signalling pathway, at the protein and RNA level. Additionally, thalidomide prevents the activation of Nuclear Factor Kappa B (NF-kB), another upstream effector of the TNF-alpha production pathway. Finally, some evidences suggest that thalidomide can block alpha-1 acid glycoprotein (AGP), a known inducer of the NF-kB/MyD88 pathway, thus inhibiting the expression of TNF-alpha. The down-regulation of NF-kB and MyD88 can also affect the cross talk between the NF-kB/MyD88 and VEGF pathway, resulting in thalidomide's anti-angiogenic effect. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. The mean time to peak plasma concentrations (T max ) ranged from 2.9 to 5.7 hours following a single dose from 50 to 400 mg. Patients with Hansen’s disease may have an increased bioavailability of thalidomide, although the clinical significance of this is unknown. Due to its low aqueous solubility and thus low dissolution is the gastrointestinal tract, thalidomide's absorption is slow, with a t lag of 20-40 min. Therefore, thalidomide exhibits absorption rate-limited pharmacokinetics or "flip-flop" phenomenon. Following a single dose of 200 mg in healthy male subjects, c max and AUC ∞ were calculated to be 2.00 ± 0.55 mg/L and 19.80 ± 3.61 mg*h/mL respectively. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of thalidomide is difficult to determine due to spontaneous hydrolysis and chiral inversion, but it is estimated to be 70-120 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The mean plasma protein binding is 55% and 66% for the (+)R and (−)S enantiomers, respectively. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Thalidomide appears to undergo primarily non-enzymatic hydrolysis in plasma to multiple metabolites, as the four amide bonds in thalidomide allow for rapid hydrolysis under physiological pH. Evidences for enzymatic metabolism of thalidomide is mixed, as in vitro studies using rat liver microsome have detected 5-hydroxythalidomide (5-OH), a monohydroxylated metabolite of thalidomide catalyzed by the CYP2C19 enzyme, and the addition of omeprazole, a CYP2C19 inhibitor, inhibits the metabolism of thalidomide. 5-hydroxythalidomide (5-OH) has also been detected in the plasma of 32% of androgen-independent prostate cancer patients undergoing oral thalidomide treatment. However, significant interspecies difference in thalidomide metabolism has been noted, potentially signifying that animals like rats and rabbits rely on enzymatic metabolism of thalidomide more than human. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Thalidomide is primarily excreted in urine as hydrolytic metabolites since less than 1% of the parent form is detected in the urine. Fecal excretion of thalidomide is minimal. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half-life of thalidomide in healthy male subjects after a single dose of 200 mg is 6.17 ± 2.56 h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The oral clearance of thalidomide is 10.50 ± 2.10 L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 in rats is 113 mg/kg and 2 g/kg in mouse. Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA). Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test. Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25- fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA). There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Thalomid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (+-)-N-(2,6-dioxo-3-Piperidyl)phthalimide (+-)-Thalidomide (±)-N-(2,6-dioxo-3-piperidyl)phthalimide (±)-thalidomide 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindoline 2,6-dioxo-3-phthalimidopiperidine 3-Phthalimidoglutarimide alpha-(N-Phthalimido)glutarimide alpha-N-Phthalylglutaramide N-(2,6-dioxo-3-piperidyl)phthalimide N-Phthaloylglutamimide N-Phthalyl-glutaminsaeure-imid N-Phthalylglutamic acid imide Talidomida (common) Thalidomide (common) Thalidomidum (common) α-(N-phthalimido)glutarimide α-N-phthalylglutaramide α-phthalimidoglutarimide

Do Abaloparatide and Thiopental interact?

•Drug A: Abaloparatide •Drug B: Thiopental •Severity: MODERATE •Description: Thiopental may increase the hypotensive activities of Abaloparatide. •Extended Description: The use of barbiturates may increase hypotension.1,2 Therefore, the concomitant administration of barbiturates and hypotensive agents may lead to dangerous hypotension due to additive effects. •References: 1. Suddock JT, Cain MD: Barbiturate Toxicity . [https://go.drugbank.com/articles/A233155] 2. Roberts I, Sydenham E: Barbiturates for acute traumatic brain injury. Cochrane Database Syst Rev. 2012 Dec 12;12(12):CD000033. doi: 10.1002/14651858.CD000033.pub2. [https://go.drugbank.com/articles/A259951] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For use as the sole anesthetic agent for brief (15 minute) procedures, for induction of anesthesia prior to administration of other anesthetic agents, to supplement regional anesthesia, to provide hypnosis during balanced anesthesia with other agents for analgesia or muscle relaxation, for the control of convulsive states during or following inhalation anesthesia or local anesthesia, in neurosurgical patients with increased intracranial pressure, and for narcoanalysis and narcosynthesis in psychiatric disorders. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Thiopental, a barbiturate, is used for the induction of anesthesia prior to the use of other general anesthetic agents and for induction of anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli. Thiopental is an ultrashort-acting depressant of the central nervous system which induces hypnosis and anesthesia, but not analgesia. It produces hypnosis within 30 to 40 seconds of intravenous injection. Recovery after a small dose is rapid, with some somnolence and retrograde amnesia. Repeated intravenous doses lead to prolonged anesthesia because fatty tissues act as a reservoir; they accumulate Pentothal in concentrations 6 to 12 times greater than the plasma concentration, and then release the drug slowly to cause prolonged anesthesia •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Thiopental binds at a distinct binding site associated with a Cl ionopore at the GABA A receptor, increasing the duration of time for which the Cl ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapidly absorbed. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Approximately 80% of the drug in the blood is bound to plasma protein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Thiopental is extensively metabolized, primarily in the liver, resulting in only 0.3% of an administered dose being excreted unchanged in the urine. Ring desulfuration leads to the generation of an active metabolite, pentobarbital, that exists in concentrations approximately 3-10% that of the parent concentration. Thiopental and pentobarbital are also subject to both oxidation and hydroxylation to carboxylic acids and alcohols, respectively, all of which are pharmacologically inert. While many of the specifics regarding thiopental biotransformation have not been elucidated, including the enzymes responsible, the oxidation of thiopental to its carboxylic acid may be the major driver of thiopental detoxification as this product appears to account for 10-25% of renally excreted drug. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 3-8 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdosage may occur from rapid or repeated injections. Too rapid injection may be followed by an alarming fall in blood pressure even to shock levels. Apnea, occasional laryngospasm, coughing and other respiratory difficulties with excessive or too rapid injections may occur. Lethal blood levels may be as low as 1 mg/100 mL for short-acting barbiturates; less if other depressant drugs or alcohol are also present. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (±)-thiopental 2-Thio-5-ethyl-5-sec-pentylbarbituric acid 5-Ethyl-5-(1-methyl-butyl)-2-thioxo-dihydro-pyrimidine-4,6-dione Penthiobarbital (common) Pentothiobarbital (common) Thiopental (common) Thiopentobarbital (common) Thiopentobarbitone (common) Thiopentobarbituric acid (common) Thiopentone (common) Tiopentale (common)

Do Abaloparatide and Thioridazine interact?

•Drug A: Abaloparatide •Drug B: Thioridazine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Thioridazine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of schizophrenia and generalized anxiety disorder. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Thioridazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Thioridazine has not been shown effective in the management of behaviorial complications in patients with mental retardation. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Thioridazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; blocks alpha-adrenergic effect, depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): 60% •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 95% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 21-25 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD 50 =956-1034 mg/kg (Orally in rats); Agitation, blurred vision, coma, confusion, constipation, difficulty breathing, dilated or constricted pupils, diminished flow of urine, dry mouth, dry skin, excessively high or low body temperature, extremely low blood pressure, fluid in the lungs, heart abnormalities, inability to urinate, intestinal blockage, nasal congestion, restlessness, sedation, seizures, shock •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 10-[2-(1-methyl-2-piperidyl)ethyl]-2-methylsulfanyl-phenothiazine 2-Methylmercapto-10-(2-(N-methyl-2-piperidyl)ethyl)phenothiazine 3-Methylmercapto-N-(2'-(N-methyl-2-piperidyl)ethyl)phenothiazine Thioridazin (common) Thioridazine (common) Thioridazinum (common) Tioridazina (common)

Do Abaloparatide and Timolol interact?

•Drug A: Abaloparatide •Drug B: Timolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Timolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Ophthalmic timolol is indicated for the treatment of increased intraocular pressure in patients with ocular hypertension or open-angle glaucoma. The oral form of this drug is used to treat high blood pressure. In certain cases, timolol is used in the prevention of migraine headaches. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Timolol, when administered by the ophthalmic route, rapidly reduces intraocular pressure. When administered in the tablet form, it reduces blood pressure, heart rate, and cardiac output, and decreases sympathetic activity.. This drug has a fast onset of action, usually occurring within 20 minutes of the administration of an ophthalmic dose. Timolol maleate can exert pharmacological actions for as long as 24 hours if given in the 0.5% or 0.25% doses. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and the beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, which normally bind to adrenergic receptors and exert sympathetic effects leading to an increase in blood pressure and heart rate. Beta(1)-receptor blockade by timolol leads to a decrease in both heart rate and cardiac output during rest and exercise, and a decrease in both systolic and diastolic blood pressure. In addition to this, a reduction in reflex orthostatic hypotension may also occur. The blockade of beta(2) receptors by timolol in the blood vessels leads to a decrease in peripheral vascular resistance, reducing blood pressure. The exact mechanism by which timolol reduces ocular pressure is unknown at this time, however, it likely decreases the secretion of aqueous humor in the eye. According to one study, the reduction of aqueous humor secretion may occur through the decreased blood supply to the ciliary body resulting from interference with the active transport system or interference with prostaglandin biosynthesis. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The systemic bioavailability of the ophthalmic eyedrop in one study of healthy volunteers was 78.0 ± 24.5%, indicating that caution must be observed when this drug is administered, as it may be significantly absorbed and have various systemic effects. Another study measured the bioavailability of timolol eyedrops to be 60% in healthy volunteers. The peak concentration of ophthalmic timolol in plasma, Cmax was about 1.14 ng/ml in most subjects within 15 minutes following the administration of timolol by the ophthalmic route. The mean area under the curve (AUC) was about 6.46 ng/ml per hour after intravenous injection and about 4.78 ng/ml per hour following eyedrop administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 1.3 - 1.7 L/kg Timolol is distributed to the following tissues: the conjunctiva, cornea, iris, sclera, aqueous humor, kidney, liver, and lung. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The plasma protein binding of timolol is not extensive and is estimated to be about 10%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Timolol is metabolized in the liver by the cytochrome P450 2D6 enzyme, with minor contributions from CYP2C19. 15-20% of a dose undergoes first-pass metabolism. Despite its relatively low first pass metabolism, timolol is 90% metabolized. Four metabolites of timolol have been identified, with a hydroxy metabolite being the most predominant. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Timolol and its metabolites are mainly found excreted in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Timolol half-life was measured at 2.9 ± 0.3 h hours in a clinical study of healthy volunteers. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): One pharmacokinetic study in healthy volunteers measured the total plasma clearance of timolol to be 557 ± 61 ml/min. Another study determined the total clearance 751.5 ± 90.6 ml/min and renal clearance to be 97.2 ± 10.1 ml/min in healthy volunteers. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD50 for timolol maleate is 1028 mg/kg in the rat and 1137 mg/kg in the mouse. Symptoms of timolol overdose may include dizziness, headache, shortness of breath, bradycardia, in addition to bronchospasm. Sometimes, an overdose may lead to cardiac arrest. An overdose of timolol can be reversed with dialysis, however, patients with renal failure may not respond as well to dialysis treatment. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Azarga, Betimol, Combigan, Cosopt, Duotrav, Istalol, Timoptic, Xalacom •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]propan-2-ol Timolol (common) Timolol anhydrous Timololo (common) Timololum (common)

Do Abaloparatide and Tizanidine interact?

•Drug A: Abaloparatide •Drug B: Tizanidine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Tizanidine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Tizanidine is indicated for the relief of muscle spasticity, which can interfere with daily activities. The general recommendation is to reserve tizanidine use for periods of time when there is a particular need for relief, as it has a short duration of action. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): A note on spasticity Spasticity is an increase in muscle accompanied by uncontrolled, repetitive contractions of skeletal muscles which are involuntary. The patient suffering from muscle spasticity may have reduced mobility and high levels of pain, contributing to poor quality of life and problems performing activities of personal hygiene and care. General effects Tizanidine is a rapidly acting drug used for the relief of muscle spasticity when it is required for performing specific activities. It acts as an agonist at Alpha-2 adrenergic receptor sites and relieves symptoms of muscle spasticity, allowing the continuation of normal daily activities. In animal models, tizanidine has not been shown to exert direct effects on skeletal muscle fibers or the neuromuscular junction, and has shown no significant effect on monosynaptic spinal reflexes (consisting of the communication between only 1 sensory neuron and 1 motor neuron). The frequency of muscle spasm and clonus are shown to be decreased by tizanidine. Tizanidine shows a stronger action on polysynaptic reflexes, which involve several interneurons (relay neurons) communicating with motor neurons stimulating muscle movement. Effects on blood pressure and heart rate This drug decreases heart rate and blood pressure in humans. Despite this, rebound hypertension and tachycardia along with increased spasticity can occur when tizanidine is abruptly discontinued. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Tizanidine reduces spasticity by causing presynaptic inhibition of motor neurons via agonist actions at Alpha-2 adrenergic receptor sites. This drug is centrally acting and leads to a reduction in the release of excitatory amino acids like glutamate and aspartate, which cause neuronal firing that leads to muscle spasm. The above reduction and excitatory neurotransmitter release results in presynaptic inhibition of motor neurons. The strongest effect of tizanidine has been shown to occur on spinal polysynaptic pathways. The anti-nociceptive and anticonvulsant activities of tizanidine may also be attributed to agonist action on Alpha-2 receptors. Tizanidine also binds with weaker affinity to the Alpha-1 receptors, explaining its slight and temporary effect on the cardiovascular system. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): This drug undergoes significant first-pass metabolism. After the administration of an oral dose, tizanidine is mostly absorbed. The absolute oral bioavailability of tizanidine is measured to be about 40%. Effect of food on absorption Food has been shown to increase absorption for both the tablets and capsules. The increase in absorption with the tablet (about 30%) was noticeably higher than the capsule (~10%). When the capsule and tablet were administered with food, the amount absorbed from the capsule was about 80% of the amount absorbed from the tablet. It is therefore advisable to take this drug with food for increased absorption, especially in tablet form. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Extensively distributed throughout the body. The average steady-state volume of distribution is 2.4 L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): About 30% bound to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): About 95% of the ingested dose of tizanidine is metabolized. The main enzyme involved in the hepatic metabolism of tizanidine is CYP1A2. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): This drug is mainly eliminated by the kidney. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Approximately 2.5 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): A note on renal impairment Tizanidine clearance is found to be decreased by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. This drug should be used with caution in patients with renal impairment. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD50 information Oral LD50 (rat): 414 mg/kg; Subcutaneous LD50 (rat): 282 mg/kg; Oral LD50 (mouse): 235 mg/kg Use in pregnancy Animal studies have determined that this drug causes fetal harm. Studies have not been performed in humans, and it is advisable to ensure that tizanidine use in pregnant women should be reserved for cases in which possible benefit clearly outweighs the possible risk to mother and unborn child. Use in breastfeeding In studies of rat models, this tizanidine was found excreted in the breastmilk with a milk-to-blood ratio of 1.8:1. In young nursing rats, abnormal results were obtained in tests indicative of central nervous system function. Various developmental changes that may have been attributable to the drug were observed. It is unknown whether tizanidine is excreted in human milk. It is a lipid-soluble drug, however, and likely to be excreted into breast milk. Carcinogenesis and mutagenesis No signs of carcinogenicity were observed in two dietary studies performed in rodent models. Tizanidine was given to mice for 78 weeks at doses reaching a maximum 16 mg/kg (equivalent to twice the maximum recommended human dose). In addition, the drug was given to rats for 104 weeks at doses reaching 9 mg/kg (equivalent to 2.5 times the maximum recommended human dose). There was a lack of a statistically significant increase in the occurrence of tumors in either study group. Tizanidine was not found to be mutagenic or clastogenic in several laboratory essays, including the bacterial Ames test, the mammalian gene mutation test, in addition to the chromosomal aberration test in Chinese hamster cells and several other assays. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Zanaflex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5-Chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole Tizanidin (common) Tizanidina (common) Tizanidine (common) Tizanidinum (common)

Do Abaloparatide and Tolcapone interact?

•Drug A: Abaloparatide •Drug B: Tolcapone •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Tolcapone is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used as an adjunct to levodopa/carbidopa therapy for the symptomatic treatment of Parkinson's Disease. This drug is generally reserved for patients with parkinsonian syndrome receiving levodopa/carbidopa who are experiencing symptom fluctuations and are not responding adequately to or are not candidates for other adjunctive therapies. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Tolcapone is a potent, selective, and reversible inhibitor of catechol-O-methyltransferase (COMT). In humans, COMT is distributed throughout various organs. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. COMT is responsible for the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's disease in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa, resulting in an increase in plasma levodopa concentrations. The inhibition of COMT also causes a reduction in circulating 3-OMD as a result of decreased peripheral metabolism of levodopa. This may lead to an increase distribution of levodopa into the CNS through the reduction of its competitive substrate, 3-OMD, for transport mechanisms. Sustained levodopa concentrations presumably result in more consistent dopaminergic stimulation, resulting in greater reduction in the manifestations of parkinsonian syndrome. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapidly absorbed (absolute bioavailability is about 65%) •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 9 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): > 99.9% (to serum albumin) •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The main metabolic pathway of tolcapone is glucuronidation •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Tolcapone is almost completely metabolized prior to excretion, with only a very small amount (0.5% of dose) found unchanged in urine. The glucuronide conjugate of tolcapone is mainly excreted in the urine but is also excreted in the bile. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 2-3.5 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 7 L/h •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD 50 = 1600 mg/kg (Orally in rats) •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Tasmar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone 3,4-dihydroxy-5-nitro-4'-methylbenzophenone 4'-methyl-3,4-dihydroxy-5-nitrobenzophenone Tolcapon (common) Tolcapona (common) Tolcapone (common) Tolcaponum (common)

Do Abaloparatide and Torasemide interact?

•Drug A: Abaloparatide •Drug B: Torasemide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Torasemide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Torasemide is indicated for the treatment of edema associated with congestive heart failure, renal or hepatic diseases. From this condition, it has been observed that torasemide is very effective in cases of kidney failure. As well, torasemide is approved to be used as an antihypertensive agent either alone or in combination with other antihypertensives. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): It is widely known that administration of torasemide can attenuate renal injury and reduce the severity of acute renal failure. This effect is obtained by increasing urine output and hence, facilitating fluid, acid-base and potassium control. This effect is obtained by the increase in the excretion of urinary sodium and chloride. Several reports have indicated that torasemide presents a long-lasting diuresis and less potassium excretion which can be explained by the effect that torasemide has on the renin-angiotensin-aldosterone system. This effect is very similar to the effect observed with the administration of combination therapy with furosemide and spironolactone and it is characterized by a decrease in plasma brain natriuretic peptide and improved measurements of left ventricular function. Above the aforementioned effect, torasemide presents a dual effect.in which the inhibition of aldosterone which donates torasemide with a potassium-sparing action. Torasemide has been shown to reduce extracellular fluid volume and blood pressure in hypertensive patients suffering from chronic kidney disease. As well, some reports have indicated that torasemide can reduce myocardial fibrosis by reducing the collagen accumulation. This effect is suggested to be related to the decrease in aldosterone which in order has been shown to reduce the production of the enzyme procollagen type I carboxy-terminal proteinase which is known to be overexpressed in heart failure patients. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): As mentioned above, torasemide is part of the loop diuretics and thus, it acts by reducing the oxygen demand in the medullary thick ascending loop of Henle by inhibiting the Na+/K+/Cl- pump on the luminal cell membrane surface. This action is obtained by the binding of torasemide to a chloride ion-binding site of the transport molecule. Torasemide is known to have an effect in the renin-angiotensin-aldosterone system by inhibiting the downstream cascade after the activation of angiotensin II. This inhibition will produce a secondary effect marked by the reduction of the expression of aldosterone synthase, TGF-B1 and thromboxane A2 and a reduction on the aldosterone receptor binding. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Torasemide is the diuretic with the highest oral bioavailability even in advanced stages of chronic kidney disease. This bioavailability tends to be higher than 80% regardless of the patient condition. The maximal serum concentration is reported to be of 1 hour and the absorption parameters are not affected by its use concomitantly with food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of torasemide is 0.2 L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Torasemide is found to be highly bound to plasma proteins, representing over 99% of the administered dose. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Torasemide is extensively metabolized in the liver and only 20% of the dose remains unchanged and it is recovered in the urine. Metabolized via the hepatic CYP2C8 and CYP2C9 mainly by reactions of hydroxylation, oxidation and reduction to 5 metabolites. The major metabolite, M5, is pharmacologically inactive. There are 2 minor metabolites, M1, possessing one-tenth the activity of torasemide, and M3, equal in activity to torasemide. Overall, torasemide appears to account for 80% of the total diuretic activity, while metabolites M1 and M3 account for 9% and 11%, respectively. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Torasemide is mainly hepatically processed and excreted in the feces from which about 70-80% of the administered dose is excreted by this pathway. On the other hand, about 20-30% of the administered dose is found in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The average half-life of torasemide is 3.5 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance rate of torasemide is considerably reduced by the presence of renal disorders. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD50 of torasemide in the rat is 5 g/kg. When overdose occurs, there is a marked diuresis with the danger of loss of fluid and electrolytes which has been seen to lead to somnolence, confusion, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, hemoconcentration dehydration and circulatory collapse. This effects can include some gastrointestinal disturbances. There is no increase in tumor incidence with torasemide and it is proven to not be mutagenic, not fetotoxic or teratogenic. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Demadex, Soaanz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-Isopropyl-3-((4-m-toluidino-3-pyridyl)sulfonyl)urea N-(((1-Methylethyl)amino)carbonyl)-4-((3-methylphenyl)amino)-3-pyridinesulfonamide Torasemida (common) Torasemide (common) Torasémide (common) Torasemidum (common) Torsemide (common)

Do Abaloparatide and Trandolapril interact?

•Drug A: Abaloparatide •Drug B: Trandolapril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Trandolapril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of mild to moderate hypertension, as an adjunct in the treatment of congestive heart failure (CHF), to improve survival following myocardial infarction (MI) in individuals who are hemodynamically stable and demonstrate symptoms of left ventricular systolic dysfunction or signs of CHF within a few days following acute MI, and to slow progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Trandolapril is the ethyl ester prodrug of a nonsulfhydryl ACE inhibitor, trandolaprilat. Trandolapril is deesterified in the liver to the diacid metabolite, trandolaprilat, which is approximately eight times more active as an inhibitor of ACE than its parent compound. ACE is a peptidyl dipeptidase that is part of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure via a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may further sustain the effects of trandolaprilat by causing increased vasodilation and decreased blood pressure. The blood pressure lowering effect of trandolaprilat is due to a decrease in peripheral vascular resistance, which is not accompanied by significant changes in urinary excretion of chloride or potassium or water or sodium retention. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Trandolaprilat, the active metabolite of trandolapril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Trandolaprilat also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): ~ 40-60% absorbed; extensive first pass metabolism results in a low bioavailability of 4-14% •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 18 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Serum protein binding of trandolapril is ~ 80% (independent of concentration and not saturable) while that of trandolaprilat is 65 to 94% (concentration-dependent and saturable). •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Cleavage of the ester group of trandolapril, primarily in the liver, is responsible for conversion to trandolaprilat, the active metabolite. Seven other metabolites, including diketopiperazine and glucuronide conjugated derivatives of trandolapril and trandolaprilat, have been identified. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After oral administration of trandolapril, about 33% of parent drug and metabolites are recovered in urine, mostly as trandolaprilat, with about 66% in feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half lives of trandolapril and trandolaprilat are about 6 and 10 hours, respectively, but, similar to all ACE inhibitors, trandolaprilat also has a prolonged terminal elimination phase that involves a small fraction of administered drug. This likely represents drug binding to plasma and tissue ACE. The effective half life of elimination for trandolaprilat is 16-24 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 52 L/h [After approximately 2 mg IV doses] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Most likely clinical manifestations of overdose are symptoms of severe hypotension. Most common adverse effects include cough, headache and dizziness. The oral LD 50 of trandolapril in mice was 4875 mg/kg in males and 3990 mg/kg in females. In rats, an oral dose of 5000 mg/kg caused low mortality (1 male out of 5; 0 females). In dogs, an oral dose of 1000 mg/kg did not cause mortality and abnormal clinical signs were not observed. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Mavik, Tarka •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Tranylcypromine interact?

•Drug A: Abaloparatide •Drug B: Tranylcypromine •Severity: MODERATE •Description: Tranylcypromine may increase the orthostatic hypotensive activities of Abaloparatide. •Extended Description: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. •References: 1. Cockhill LA, Remick RA: Blood pressure effects of monoamine oxidase inhibitors--the highs and lows. Can J Psychiatry. 1987 Dec;32(9):803-8. [https://go.drugbank.com/articles/A36302] 2. Remick RA, Froese C: Monoamine oxidase inhibitors: clinical review. Can Fam Physician. 1990 Jun;36:1151-5. [https://go.drugbank.com/articles/A36361] 3. Delini-Stula A, Baier D, Kohnen R, Laux G, Philipp M, Scholz HJ: Undesirable blood pressure changes under naturalistic treatment with moclobemide, a reversible MAO-A inhibitor--results of the drug utilization observation studies. Pharmacopsychiatry. 1999 Mar;32(2):61-7. doi: 10.1055/s-2007-979193. [https://go.drugbank.com/articles/A36609] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of major depressive episode without melancholia. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Tranylcypromine belongs to a class of antidepressants called monoamine oxidase inhibitors (MAOIs). Tranylcypromine is a non-hydrazine monoamine oxidase inhibitor with a rapid onset of activity. MAO is an enzyme that catalyzes the oxidative deamination of a number of amines, including serotonin, norepinephrine, epinephrine, and dopamine. Two isoforms of MAO, A and B, are found in the body. MAO-A is mainly found within cells located in the periphery and catalyzes the breakdown of serotonin, norepinephrine, epinephrine, dopamine and tyramine. MAO-B acts on phenylethylamine, norepinephrine, epinephrine, dopamine and tyramine, is localized extracellularly and is found predominantly in the brain. While the mechanism of MAOIs is still unclear, it is thought that they act by increasing free serotonin and norepinephrine concentrations and/or by altering the concentrations of other amines in the CNS. It has been postulated that depression is caused by low levels of serotonin and/or norepinephrine and that increasing serotonergic and norepinephrinergic neurotransmission results in relief of depressive symptoms. MAO A inhibition is thought to be more relevant to antidepressant activity than MAO B inhibition. Selective MAO B inhibitors, such as selegiline, have no antidepressant effects. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Tranylcypromine irreversibly and nonselectively inhibits monoamine oxidase (MAO). Within neurons, MAO appears to regulate the levels of monoamines released upon synaptic firing. Since depression is associated with low levels of monoamines, the inhibition of MAO serves to ease depressive symptoms, as this results in an increase in the concentrations of these amines within the CNS. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Interindividual variability in absorption. May be biphasic in some individuals. Peak plasma concentrations occur in one hour following oral administration with a secondary peak occurring within 2-3 hours. Biphasic absorption may represent different rates of absorption of the stereoisomers of the drug, though additional studies are required to confirm this. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 1.1-5.7 L/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 1.5-3.2 hours in patients with normal renal and hepatic function •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): In overdosage, some patients exhibit insomnia, restlessness and anxiety, progressing in severe cases to agitation, mental confusion and incoherence. Hypotension, dizziness, weakness and drowsiness may occur, progressing in severe cases to extreme dizziness and shock. A few patients have displayed hypertension with severe headache and other symptoms. Rare instances have been reported in which hypertension was accompanied by twitching or myoclonic fibrillation of skeletal muscles with hyperpyrexia, sometimes progressing to generalized rigidity and coma. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Parnate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (±)-trans-2-phenylcyclopropylamine (1R*,2S*)-2-phenylcyclopropan-1-amine dl-tranylcypromine (common) Racemic Tranylcypromine (common) Tranilcipromina (common) trans-2-phenylcyclopropylamine trans-DL-2-Phenylcyclopropylamine Transamine (common) Tranylcypromin (common) Tranylcypromine (common) Tranylcyprominum (common)

Do Abaloparatide and Treprostinil interact?

•Drug A: Abaloparatide •Drug B: Treprostinil •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Treprostinil. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •References: 1. Lee CH, Strosberg AM, Carver LA: Antihypertensive drugs: their postural hypotensive effect and their blood pressure lowering activity in conscious normotensive rats. Arch Int Pharmacodyn Ther. 1983 Jan;261(1):90-101. [https://go.drugbank.com/articles/A177104] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): The FDA has indicated treprostinil for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease to improve exercise ability. It is also used to treat pulmonary arterial hypertension in patients requiring transition from epoprostenol. The Health Canada label specifies that treprostinil is indicated for the long-term treatment of pulmonary arterial hypertension in NYHA Class III and IV patients who did not respond adequately to conventional therapy. L24244 •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): As an analogue of prostacyclin, treprostinil promotes the vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In animals, the vasodilatory effects of treprostinil lead to a reduction of right and left ventricular afterload and an increase in cardiac output and stroke volume. Treprostinil also causes a dose-related negative inotropic and lusitropic effect, and no major effects on cardiac conduction have been detected. Short-lasting effects on QTc were detected in healthy volunteers (n=240) given inhaled single doses of 54 and 84 μg of treprostinil. These effects dissipated rapidly as treprostinil concentrations lowered. When given subcutaneously or intravenously, treprostinil has the potential to reach higher concentrations. The effect of oral treprostinil on QTc has not been evaluated. Due to its ability to inhibit platelet aggregation, treprostinil can increase the risk of bleeding, and patients with low systemic arterial pressure taking treprostinil may experience symptomatic hypotension. The abrupt withdrawal of treprostinil or drastic changes in dose may worsen the symptoms of pulmonary arterial hypertension (PAH). The inhalation of treprostinil can also cause bronchospasms in patients with asthma, chronic obstructive pulmonary disease (COPD), or bronchial hyperreactivity. When given intravenously, treprostinil can lead to infusion complications and increase the risk of bloodstream infections. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Treprostinil is a stable analogue of prostacyclin, a prostaglandin that acts as an anti-thrombotic agent and a potent vasodilator. Prostacyclin analogues are useful in the treatment of pulmonary arterial hypertension (PAH), a disease characterized by abnormally high blood pressure in the arteries between the heart and lungs. PAH leads to right heart failure due to the remodelling of pulmonary arteries, and patients with this condition have a poor prognosis. Treprostinil binds and activates the prostacyclin receptor, the prostaglandin D2 receptor 1, and the prostaglandin E2 receptor 2. The activation of these receptors leads to the elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, which consequently promotes the opening of calcium-activated potassium channels that lead to cell hyperpolarization. This mechanism promotes the direct vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In addition to its direct vasodilatory effects, treprostinil inhibits inflammatory pathways. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): After subcutaneous infusion, treprostinil is completely absorbed, with a bioavailability of about 100%, and it reaches steady-state concentrations in approximately 10 hours. The pharmacokinetics of treprostinil follow a two-compartment model and are linear between 2.5 and 125 ng/kg/min. Subcutaneous and intravenous doses of treprostinil are bioequivalent at 10 ng/kg/min. Compared to healthy subjects, patients with mild and moderate hepatic insufficiency had a corresponding C max 2- and 4-times higher and an AUC 0-∞ 3- and 5-times higher when given a subcutaneous treprostinil dose of 10 ng/kg/min for 150 min. When given orally at doses between 0.5 and 15 mg twice a day, treprostinil follows a dose-proportional pharmacokinetic profile. The oral bioavailability of treprostinil is 17%, and drug concentration reaches its highest level between 4 and 6 hours after oral administration. The oral absorption of treprostinil is affected by food. The AUC and C max of oral treprostinil increase 49% and 13%, respectively, when this drug is administered with a high-fat, high-calorie meal. The AUC and C max of inhaled treprostinil were proportional to the doses administered (18 to 90 μg). The bioavailability of inhaled treprostinil was 64% in patients receiving 2 doses of 18 μg, and 72% in patients receiving two doses of 36 μg. Two separate studies that evaluated the pharmacokinetics of inhaled treprostinil at a maintenance dose of 54 μg found that the mean C max was 0.91 and 1.32 ng/mL, respectively, with a corresponding T max of 0.25 and 0.12 hr and a mean AUC of 0.81 and 0.97 hr⋅ng/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of treprostinil is 14 L/70 kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): At in vitro concentrations ranging from 330 to 10,000 μg/L, the human plasma protein binding of treprostinil is approximately 91%. This concentration is above what is considered to be clinically relevant. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Treprostinil is mostly metabolized by the liver, mainly by CYP2C8, and by CYP2C9 to a lesser extent. Treprostinil does not have a single major metabolite. The five metabolites detected in urine (HU1 through HU5) accounted for 13.8, 14.3, 15.5, 10.6 and 10.2% of the dose, respectively. One of the metabolites (HU5) is the glucuronide conjugate of treprostinil. HU1, HU2, HU3 and HU4 are formed through the oxidation of the 3-hydroxyloctyl side chain. None of the metabolites of treprostinil appear to be active. In vitro studies suggest that treprostinil does not inhibit or induce any major CYP enzymes. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Treprostinil metabolites are excreted through urine (79%) and feces (13%) over 10 days. Only a small proportion of treprostinil is excreted unchanged. When administered orally, 1.13% and 0.19% of unchanged treprostinil diolamine are found in urine and feces, respectively. When administered subcutaneously, intravenously or by inhalation, 4% of unchanged treprostinil is found in urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half-life of treprostinil is approximately 4 hours, following a two-compartment model. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of treprostinil is 30 L/hr in a 70 kg person. In patients with mild to moderate hepatic insufficiency, clearance is reduced up to 80%. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Treprostinil overdose symptoms are an extension of its dose-limiting pharmacologic effects. These include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most overdose events were self-limiting and resolved by reducing or withholding treprostinil. In studies where treprostinil was infused using an external pump, several patients received an overdose due to an accidental bolus administration, errors in the programmed delivery rate and incorrect prescriptions. Only two cases of of substantial hemodynamic concern were detected among patients that received an excess of treprostinil. A pediatric patient that accidentally received 7.5 mg of treprostinil via a central venous catheter presented flushing, headache, nausea, vomiting, hypotension, and seizure-like activity with loss of consciousness for several minutes. A rat study that evaluated the carcinogenic effects of inhaled treprostinil, found no evidence of carcinogenicity in levels up to 35 times the clinical exposure obtained with a maintenance dose of 54 μg. The infusion of treprostinil sodium did not affect fertility or mating performance in rats given subcutaneous treprostinil. Treprostinil did not show mutagenic or clastogenic effects in in vitro or in vivo studies. There was no significant increase of tumors in rats given up to 10 mg/kg/day of oral treprostinil diolamine. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Orenitram, Remodulin, Tyvaso •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Triamterene interact?

•Drug A: Abaloparatide •Drug B: Triamterene •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Triamterene is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Triamterene is indicated for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and the nephrotic syndrome; also in steroid-induced edema, idiopathic edema, and edema due to secondary hyperaldosteronism. Triamterene in combination with hydrochlorothiazide is indicated for the managment of hypertension or treatment of edema in patients who develop hypokalemia following hydrochlorothiazide monotherapy, and in patients who require thiazide diuretic and in whom the development of hypokalemia cannot be risked. Triamterene allows the maintenance of potassium balance when given in combination with loop diuretics and thiazides. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Triamterene, a relatively weak, potassium-sparing diuretic and antihypertensive, is used in the management of hypertension and edema. It primarily works on the distal nephron in the kidneys; it acts from the late distal tubule to the collecting duct to inhibit Na+ reabsorption and decreasing K+ excretion. As triamterene tends to conserve potassium more strongly than promoting Na+ excretion, it can cause an increase in serum potassium, which may result in hyperkalemia potentially associated with cardiac irregularities. In healthy volunteers administered with oral triamterene, there was an increase in the renal clearnace of sodium and magnesium, and a decrease in the clearance of uric acid and creatinine due to its effect of reducing glomerular filtration renal plasma flow. Triamterene does not affect calcium excretion. In clinical trials, the use of triamterene in combination with hydrochlorothiazide resulted an enhanced blood pressure-lowering effects of hydrochlorothiazide. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Triamterene inhibits the epithelial sodium channels (ENaC) located on the lumenal side in the late distal convoluted tubule and collecting tubule, which are transmembrane channels that normally promote sodium uptake and potassium secretion. In the late distal tubule to the collecting duct, sodium ions are actively reabsorbed via ENaC on the luminal membrane and are extruded out of the cell into the peritubular medium by a sodium-potassium exchange pump, the Na-K-ATPase, with water following passively. Triamterene exerts a diuretic effect on the distal renal tubule to inhibit the reabsorption of sodium ions in exchange for potassium and hydrogen ions and its natriuretic activity is limited by the amount of sodium reaching its site of action. Its action is antagonistic to that of adrenal mineralocorticoids, such as aldosterone, but it is not an inhibitor or antagonist of aldosterone. Triamterene maintains or increases sodium excretion, thereby increasing the excretion of water, and reducing the excess loss of potassium, hydrogen, and chloride ions by inhibiting the distal tubular exchange mechanism. Due to its diuretic effect, triamterene rapidly and reversibly reduces the lumen-negative transepithelial potential difference by almost completely abolishing Na+ conductance without altering K+ conductance. This reduces the driving force for potassium movement into the tubular lumen and thus decreases potassium excretion. Triamterene is similar in action to amiloride but, unlike amiloride, increases the urinary excretion of magnesium. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Triamterene is shown to be rapidly absorbed in the gastrointestinal tract Its onset of action achiveved within 2 to 4 hours after oral ingestion and its duration of action is 12-16 hours. It is reported that the diuretic effect of triamterene may not be observed for several days after administration. In a pharmacokinetic study, the oral bioavailability of triamterene was determined to be 52%. Following administration of a single oral dose to fasted healthy male volunteers, the mean AUC of triamterene was about 148.7 ng*hr/mL and the mean peak plasma concentrations (Cmax) were 46.4 ng/mL reached at 1.1 hour after administration. In a limited study, administration of triamterene in combination with hydrochlorothiazide resulted in an increased bioavailability of triamterene by about 67% and a delay of up to 2 hours in the absorption of the drug. It is advised that triamterene is administered after meals; in a limited study, combination use of triamterene and hydrochlorothiazide with the consumption of a high-fat meal resulted in an increase in the mean bioavailability and peak serum concentrations of triamterene and its active sulfate metabolite, as well as a delay of up to 2 hours in the absorption of the active constituents. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): In a pharmacolinetic study involving healthy volunteers receiving triamterene intravenously, the volumes of distribution of the central compartment of triamterene and its hydroxylated ester metabolite were 1.49 L/kg and 0.11 L/kg, respectively. Triamterene was found to cross the placental barrier and appear in the cord blood of animals. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 67% bound to proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Triamterene undergoes phase I metabolism involving hydroxylation, via CYP1A2 activity, to form 4'-hydroxytriamterene. 4'-Hydroxytriamterene is further transformed in phase II metabolism mediated by cytosolic sulfotransferases to form the major metabolite, 4′-hydroxytriamterene sulfate, which retains a diuretic activity. Both the plasma and urine levels of this metabolite greatly exceed triamterene levels while the renal clearance of the sulfate conjugate was les than that of triamterene; this low renal clearance of the sulfate conjugate as compared with triamterene may be explained by the low unbound fraction of the metabolite in plasma. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Triamterene and its metabolites are excreted by the kidney by filtration and tubular secretion. Upon oral ingestion, somewhat less than 50% of the oral dose reaches the urine. About 20% of an oral dose appears unchanged in the urine, 70% as the sulphate ester of hydroxytriamterene and 10% as free hydroxytriamterene and triamterene glucuronide. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half-life of the drug in plasma ranges from 1.5 to 2 hours. In a pharmacokinetic study involving healthy volunteers, the terminal half-lives for triamterene and 4′-hydroxytriamterene sulfate were 255 ± 42 and 188 ± 70 minutes, respectively, after intravenous infusion of the parent drug. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The total plasma clearance was 4.5 l/min and renal plasma clearance was 0.22 l/kg following intravenous administration of triamterene in healthy volunteers. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Acute oral LD50 of triamterene in rats is 400 mg/kg and 285-380 mg/kg in mice. There has been a case of reversible acute renal failure following ingestion of 50 combination pills containing 50 mg triamterene and 25 mg hydrochlorothiazide. Symptoms of overdose, such as nausea, vomiting, gastrointestinal disturbances, weakness, and hypotension, are related to electrolyte imbalances, such as hyperkalemia. As there is no specific antidote, emesis and gastric lavage should be use to induce immediate evacuation of the stomach and careful evaluation of the electrolyte pattern and fluid balance should be made. Dialysis may be somewhat effective in case of an overdosage. In a carciongenicity study in male and female mice administered with triamterene at the highst dosage level, there was an increased incidence of hepatocellular neoplasia, primarily adenomas. However, this was not a dose-dependent phenomenon and there was no statistically significant difference from control incidence at any dose level. In bacterial assays, there was no demonstrated mutagenic potential of triamterene. In in vitro assay using Chinese hamster ovary (CHO) cells with or without metabolic activation, there were no chromosomal aberrations. Studies evaluating the effects of triamterene on reproductive system or fertility have not been conducted. It is advised that the use of triamterene is avoided during pregnancy. As triamterene has been detected in human breast milk, triamterene should be used when nursing is ceased. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Dyrenium, Maxzide •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 6-phenylpteridine-2,4,7-triamine Teridin (common) Triamteren (common) Triamterena (common) Triamtérène (common) Triamterene (common) Triamtereno (common) Triamterenum (common)

Do Abaloparatide and Udenafil interact?

•Drug A: Abaloparatide •Drug B: Udenafil •Severity: MINOR •Description: The risk or severity of hypotension can be increased when Udenafil is combined with Abaloparatide. •Extended Description: The subject drug is a phosphodiesterase 5 inhibitor which can lower blood pressure.1 The affected drug can cause hypotension, particularly orthostatic hypotension. Concomitant administration of these medications may lead to an increased risk of hypotension and orthostatic hypotension. •References: 1. Schwartz BG, Kloner RA: Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation. 2010 Jul 6;122(1):88-95. doi: 10.1161/CIRCULATIONAHA.110.944603. [https://go.drugbank.com/articles/A33630] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Investigated for use/treatment in erectile dysfunction and hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Udenafil is a potent selective phosphodiesterase type 5 (PDE5) inhibitor. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Udenafil inhibits the cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) by udenafil enhances erectile function by increasing the amount of cGMP. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. Metabolized by CYP3A4 and CYP3A5. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Valsartan interact?

•Drug A: Abaloparatide •Drug B: Valsartan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Valsartan is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Valsartan is indicated for the treatment of hypertension to reduce the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. It is also indicated for the treatment of heart failure (NYHA class II-IV) and for left ventricular dysfunction or failure after myocardial infarction when the use of an angiotensin-converting enzyme inhibitor (ACEI) is not appropriate. It is also used in combination with sacubitril. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Valsartan inhibits the pressor effects of angiotensin II with oral doses of 80 mg inhibiting the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan. In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid. Hypotension Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with valsartan alone. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision. Caution should be observed when initiating therapy in patients with heart failure. Patients with heart failure given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Impaired Renal Function Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan. Hyperkalemia Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of valsartan may be required. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Valsartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which selectively bind to angiotensin receptor 1 (AT1) and prevent angiotensin II from binding and exerting its hypertensive effects. These include vasoconstriction, stimulation and synthesis of aldosterone and ADH, cardiac stimulation, and renal reabsorption of sodium among others. Overall, valsartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium. Valsartan also affects the renin-angiotensin aldosterone system (RAAS), which plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and prevent ventricular hypertrophy. The angiotensin-converting enzyme inhibitor (ACEI) class of medications (which includes drugs such as ramipril, lisinopril, and perindopril ) inhibits the conversion of angiotensin I to angiotensin II by inhibiting the ACE enzyme but does not prevent the formation of all angiotensin II. ARB activity is unique in that it blocks all angiotensin II activity, regardless of where or how it was synthesized. Valsartan is commonly used for the management of hypertension, heart failure, and type 2 diabetes-associated nephropathy, particularly in patients who are unable to tolerate ACE inhibitors. ARBs such as valsartan have been shown in a number of large-scale clinical outcomes trials to improve cardiovascular outcomes including reducing risk of myocardial infarction, stroke, the progression of heart failure, and hospitalization. Valsartan also slows the progression of diabetic nephropathy due to its renoprotective effects. Improvements in chronic kidney disease with valsartan include both clinically and statistically significant decreases in urinary albumin and protein excretion in patients diagnosed with type 2 diabetes and in nondiabetic patients diagnosed with chronic kidney disease. Valsartan also binds to the AT2 receptor, however AT2 is not known to be associated with cardiovascular homeostasis like AT1. Valsartan has about 20,000-fold higher affinity for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): After one oral dose, the antihypertensive activity of valsartan begins within approximately 2 hours and peaks within 4-6 hours in most patients. Food decreases the exposure to orally administered valsartan by approximately 40% and peak plasma concentration by approximately 50%. AUC and Cmax values of valsartan generally increase linearly with increasing dose over the therapeutic dose range. Valsartan does not accumulate appreciably in plasma following repetitive administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The steady-state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Valsartan is highly bound to serum proteins (95%), mainly serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Valsartan undergoes minimal liver metabolism and is not biotransformed to a high degree, as only approximately 20% of a single dose is recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): After intravenous (IV) administration, valsartan demonstrates bi-exponential decay kinetics, with an average elimination half-life of about 6 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Following intravenous administration, plasma clearance of valsartan is approximately 2 L/hour and its renal clearance is 0.62 L/hour (about 30% of total clearance). •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Approximate LD50 >2000 mg/kg (Gavage, rat) Reproductive Toxicology Studies No teratogenic effects were seen when valsartan was given to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses reaching up to 10 mg/kg/day. Despite this, marked decreases in fetal weight, pup birth weight, pup survival rate, and delays in developmental milestones were noted in studies in which parental rats were treated with valsartan at oral, maternally toxic doses of 600 mg/kg/day during the organogenesis period or during late gestation and lactation. Pregnancy When used in pregnancy, drugs that act directly on the renin-angiotensin system (RAAS) can cause injury and death to the developing fetus. When pregnancy is detected, valsartan should be discontinued as soon as possible. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Dafiro, Diovan, Diovan Hct, Entresto, Exforge, Exforge Hct •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-N-Valeryl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl}-valine N-(P-(O-1H-Tetrazol-5-ylphenyl)benzyl)-N-valeryl-L-valine N-pentanoyl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valine Valsartan (common)

Do Abaloparatide and Vardenafil interact?

•Drug A: Abaloparatide •Drug B: Vardenafil •Severity: MINOR •Description: The risk or severity of hypotension can be increased when Vardenafil is combined with Abaloparatide. •Extended Description: The subject drug is a phosphodiesterase 5 inhibitor which can lower blood pressure.1 The affected drug can cause hypotension, particularly orthostatic hypotension. Concomitant administration of these medications may lead to an increased risk of hypotension and orthostatic hypotension. •References: 1. Schwartz BG, Kloner RA: Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation. 2010 Jul 6;122(1):88-95. doi: 10.1161/CIRCULATIONAHA.110.944603. [https://go.drugbank.com/articles/A33630] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Vardenafil is indicated for the treatment of erectile dysfunction. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Vardenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), an enzyme responsible for the degradation of cGMP in the corpus cavernosum. The presence of cGMP in the corpus cavernosum leads to smooth muscle relaxation, an increased inflow of blood and an erection. Therefore, in patients with erectile dysfunction given vardenafil, normal sexual stimulation will increase cGMP levels in the corpus cavernosum. Without sexual stimulation and no cGMP production, vardenafil should not cause an erection. Vardenafil should not be used in men for whom sexual activity is not recommended due to their underlying cardiovascular status. There is also a risk of developing prolonged erections that last longer than 4 hours, as well as priapism. In the event of a sudden loss of vision in one or both eyes, patients should stop using vardenafil. Patients taking PDE5 inhibitors, such as vardenafil, may also develop sudden hearing loss and experience a prolonged QT interval. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Vardenafil inhibits cyclic guanosine monophosphate (GMP) specific phosphodiesterase type 5 (PDE5), which is responsible for the degradation of cyclic GMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cyclic GMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The tissue concentration of cyclic GMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs), and the most abundant PDE in the human corpus cavernosum is PDE5. Therefore, the inhibition of PDE5 by vardenafil enhances erectile function by increasing the amount of cyclic GMP. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Over the recommended dose range, vardenafil has a dose-proportional pharmacokinetics profile. In healthy male volunteers given a single oral dose of 20 mg of vardenafil, maximum plasma concentrations were reached between 30 minutes and 2 hours (median 60 minutes) after oral dosing in the fasted state, and 0.00018% of the dose was detected in semen 1.5 hours after dosing. Vardenafil has a bioavailability of approximately 15%. High-fat meals cause a C max reduction of 18%-50%; however, no changes were detected in AUC or T max. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Vardenafil has a steady-state volume of distribution of 208 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Approximately 95% of vardenafil and its major circulating metabolite is bound to plasma proteins. Their protein binding is reversible and independent of total drug concentrations. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Vardenafil is mainly metabolized by CYP3A4 in the liver, although CYP3A5 and CYP2C isoforms also contribute to its metabolism. The major circulating metabolite, M1 (N-desethylvardenafil), results from desethylation at the piperazine moiety of vardenafil, and has a plasma concentration of approximately 26% of that of the parent compound. M1 has a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Vardenafil is excreted as metabolites mainly through feces and urine. Approximately 91-95% of administered oral dose is found in feces, while 2-6% of administered oral dose is found in urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Vardenafil and its primary metabolite (M1) have a terminal half-life of 4-5 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Vardenafil has a total body clearance of 56 L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Healthy male volunteers given a single dose of 120 mg of vardenafil experienced reversible back pain, myalgia and abnormal vision. Patients given vardenafil once daily over 4 weeks in single doses up to 80 mg and multiple doses up to 40 mg did not present serious adverse side effects. Cases of severe back pain were observed when 40 mg of vardenafil was administered twice daily; however patients did not present muscle or neurological toxicity. In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to accelerate clearance as vardenafil is highly bound to plasma proteins and not significantly eliminated in the urine. No carcinogenic effects were detected in rats and mice given vardenafil daily for 24 months. Vardenafil was not mutagenic or clastogenic, and did not have an effect in fertility in male and female rats given up to 100 mg/kg/day for 28 days prior to mating in males, and for 14 days prior to mating and through day 7 of gestation in females. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Levitra, Staxyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Verapamil interact?

•Drug A: Abaloparatide •Drug B: Verapamil •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Verapamil is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Verapamil is indicated in the treatment of vasopastic (i.e. Prinzmetal's) angina, unstable angina, and chronic stable angina. It is also indicated to treat hypertension, for the prophylaxis of repetitive paroxysmal supraventricular tachycardia, and in combination with digoxin to control ventricular rate in patients with atrial fibrillation or atrial flutter. Given intravenously, it is indicated for the treatment of various supraventricular tachyarrhythmias, including rapid conversion to sinus rhythm in patients with supraventricular tachycardia and for temporary control of ventricular rate in patients with atrial fibrillation or atrial flutter. Verapamil is commonly used off-label for prophylaxis of cluster headaches. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Verapamil is an L-type calcium channel blocker with antiarrhythmic, antianginal, and antihypertensive activity. Immediate-release verapamil has a relatively short duration of action, requiring dosing 3 to 4 times daily, but extended-release formulations are available that allow for once-daily dosing. As verapamil is a negative inotropic medication (i.e. it decreases the strength of myocardial contraction), it should not be used in patients with severe left ventricular dysfunction or hypertrophic cardiomyopathy as the decrease in contractility caused by verapamil may increase the risk of exacerbating these pre-existing conditions. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Verapamil inhibits L-type calcium channels by binding to a specific area of their alpha-1 subunit, Cav1.2, which is highly expressed on L-type calcium channels in vascular smooth muscle and myocardial tissue where these channels are responsible for the control of peripheral vascular resistance and heart contractility. Calcium influx through these channels allows for the propagation of action potentials necessary for the contraction of muscle tissue and the heart's electrical pacemaker activity. Verapamil binds to these channels in a voltage- and frequency-dependent manner, meaning affinity is increased 1) as vascular smooth muscle membrane potential is reduced, and 2) with excessive depolarizing stimulus. Verapamil's mechanism of action in the treatment of angina and hypertension is likely due to the mechanism described above. Inhibition of calcium influx prevents the contraction of vascular smooth muscle, causing relaxation/dilation of blood vessels throughout the peripheral circulation - this lowers systemic vascular resistance (i.e. afterload) and thus blood pressure. This reduction in vascular resistance also reduces the force against which the heart must push, decreasing myocardial energy consumption and oxygen requirements and thus alleviating angina. Electrical activity through the AV node is responsible for determining heart rate, and this activity is dependent upon calcium influx through L-type calcium channels. By inhibiting these channels and decreasing the influx of calcium, verapamil prolongs the refractory period of the AV node and slows conduction, thereby slowing and controlling the heart rate in patients with arrhythmia. Verapamil's mechanism of action in the treatment of cluster headaches is unclear, but is thought to result from an effect on other calcium channels (e.g. N-, P-, Q-, or T-type). Verapamil is known to interact with other targets, including other calcium channels, potassium channels, and adrenergic receptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): More than 90% of orally administered verapamil is absorbed - despite this, bioavailability ranges only from 20% to 30% due to rapid biotransformation following first-pass metabolism in the portal circulation. Absorption kinetic parameters are largely dependent on the specific formulation of verapamil involved. Immediate-release verapamil reaches peak plasma concentrations (i.e. T max ) between 1-2 hours following administration, whereas sustained-release formulations tend to have a T max between 6 - 11 hours. AUC and C max values are similarly dependent upon formulation. Chronic administration of immediate-release verapamil every 6 hours resulted in plasma concentrations between 125 and 400 ng/mL. Steady-state AUC 0-24h and C max values for a sustained-release formulation were 1037 ng∙h/ml and 77.8 ng/mL for the R-isomer and 195 ng∙h/ml and 16.8 ng/mL for the S-isomer, respectively. Interestingly, the absorption kinetics of verapamil are highly stereospecific - following oral administration of immediate-release verapamil every 8 hours, the relative systemic availability of the S-enantiomer compared to the R-enantiomer was 13% after a single dose and 18% at steady-state. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Verapamil has a steady-state volume of distribution of approximately 300L for its R-enantiomer and 500L for its S-enantiomer. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Verapamil is extensively protein-bound in plasma. R-verapamil is 94% bound to serum albumin while S-verapamil is 88% bound. Additionally, R-verapamil is 92% bound to alpha-1 acid glycoprotein and S-verapamil is 86% bound. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Verapamil is extensively metabolized by the liver, with up to 80% of an administered dose subject to elimination via pre-systemic metabolism - interestingly, this first-pass metabolism appears to clear the S-enantiomer of verapamil much faster than the R-enantiomer. The remaining parent drug undergoes O-demethylation, N-dealkylation, and N-demethylation to a number of different metabolites via the cytochrome P450 enzyme system. Norverapamil, one of the major circulating metabolites, is the result of verapamil's N-demethylation via CYP2C8, CYP3A4, and CYP3A5, and carries approximately 20% of the cardiovascular activity of its parent drug. The other major pathway involved in verapamil metabolism is N-dealkylation via CYP2C8, CYP3A4, and CYP1A2 to the D-617 metabolite. Both norverapamil and D-617 are further metabolized by other CYP isoenzymes to various secondary metabolites. CYP2D6 and CYP2E1 have also been implicated in the metabolic pathway of verapamil, albeit to a minor extent. Minor pathways of verapamil metabolism involve its O-demethylation to D-703 via CYP2C8, CYP2C9, and CYP2C18, and to D-702 via CYP2C9 and CYP2C18. Several steps in verapamil's metabolic pathway show stereoselective preference for the S-enantiomer of the given substrate, including the generation of the D-620 metabolite by CYP3A4/5 and the D-617 metabolite by CYP2C8. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 70% of an administered dose is excreted as metabolites in the urine and ≥16% in the feces within 5 days. Approximately 3% - 4% is excreted in the urine as unchanged drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Single-dose studies of immediate-release verapamil have demonstrated an elimination half-life of 2.8 to 7.4 hours, which increases to 4.5 to 12.0 hours following repetitive dosing. The elimination half-life is also prolonged in patients with hepatic insufficiency (14 to 16 hours) and in the elderly (approximately 20 hours). Intravenously administered verapamil has rapid distribution phase half-life of approximately 4 minutes, followed by a terminal elimination phase half-life of 2 to 5 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Systemic clearance following 3 weeks of continuous treatment was approximately 340 mL/min for R-verapamil and 664 mL/min for S-verapamil. Of note, apparent oral clearance appears to vary significantly between single dose and multiple-dose conditions. The apparent oral clearance following single doses of verapamil was approximately 1007 mL/min for R-verapamil and 5481 mL/min for S-verapamil, whereas 3 weeks of continuous treatment resulted in apparent oral clearance values of approximately 651 mL/min for R-verapamil and 2855 mL/min for S-verapamil. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Verapamil's reported oral TDLo is 14.4 mg/kg in women and 3.429 mg/kg in men. The oral LD 50 is 150 mg/kg in rats and 163 mg/kg in mice. As there is no antidote for verapamil overdosage, treatment is largely supportive. Symptoms of overdose are generally consistent with verapamil's adverse effect profile (i.e. hypotension, bradycardia, arrhythmia) but instances of non-cardiogenic pulmonary edema have been observed following ingestion of large overdoses (up to 9 grams). In acute overdosage, consider the use of gastrointestinal decontamination with cathartics and/or bowel irrigation. Patients presenting with significant myocardial depression may require intravenous calcium, atropine, vasopressors, or other inotropes. Consider the formulation responsible for the overdose prior to treatment - sustained-release formulations may result in delayed pharmacodynamic effects, and these patients should be monitored closely for at least 48 hours following ingestion. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Calan, Isoptin, Tarka, Verelan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Vericiguat interact?

•Drug A: Abaloparatide •Drug B: Vericiguat •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Vericiguat. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •References: 1. Elliott WJ: Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006 Oct;8(10):731-7. [https://go.drugbank.com/articles/A31840] 2. Chamontin B, Amar J: [https://go.drugbank.com/articles/A34541] 3. Schoenberger JA: Drug-induced orthostatic hypotension. Drug Saf. 1991 Nov-Dec;6(6):402-7. [https://go.drugbank.com/articles/A37420] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Vericiguat is indicated in adults with symptomatic, chronic heart failure and an ejection fraction of <45% to reduce the risk of cardiovascular death and heart failure-related hospitalization following a hospitalization for heart failure or need for outpatient intravenous diuretics. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): By directly stimulating the increased production of intracellular cyclic guanosine monophosphate (cGMP), vericiguat causes the relaxation of vascular smooth muscle and vasodilation. Vericiguat has a relatively long half-life (~30h) that allows for once-daily dosing. Animal reproduction studies have demonstrated the potential for embryo-fetal toxicity when vericiguat is administered to pregnant females - defects in major vessel and heart formation, as well as spontaneous abortions/resorptions, were observed when vericiguat was administered to pregnant rabbits during organogenesis. The possibility of pregnancy should be excluded prior to beginning therapy with vericiguat, and adequate contraception should be used throughout therapy and for one month following cessation of treatment. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Heart failure (HF) involves, amongst other morphologic and physiologic changes, the impaired synthesis of nitric oxide (NO) and decreased activity of soluble guanylate cyclase (sGC). Functioning normally, NO binds to sGC and stimulates the synthesis of intracellular cyclic guanosine monophosphate (cGMP), a second messenger involved in the maintenance of vascular tone, as well as cardiac contractility and remodeling. Defects in this pathway are thought to contribute to the myocardial and vascular dysfunction associated with heart failure and are therefore a desirable target in its treatment. Vericiguat directly stimulates sGC by binding to a target site on its beta-subunit, bypassing the need for NO-mediated activation, and in doing so causes an increase in the production of intracellular cGMP that results in vascular smooth muscle relaxation and vasodilation. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following the administration of 10mg of vericiguat by mouth once daily, the average steady-state C max and AUC in patients with heart failure is 350 mcg/L and 6,680 mcg•h/L, respectively, with a T max of 1 hour. The absolute bioavailability of orally-administered vericiguat is approximately 93% when taken with food - co-administration with meals has been shown to reduce pharmacokinetic variability, increase T max to roughly 4 hours, and increase C max and AUC by 41% and 44%, respectively. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): In healthy subjects the steady-state volume of distribution of vericiguat is approximately 44 liters. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Vericiguat is extensively (~98%) protein-bound in plasma, primarily to serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Vericiguat is primarily metabolized via phase II conjugation reactions, with CYP-mediated oxidative metabolism comprising a small (<5%) portion of its overall biotransformation. The major inactive metabolite, vericiguat N-glucuronide (M1), is formed by UGT1A9 and, to a lesser extent, UGT1A1. Other identified metabolites include a denbenzylated compound and an M15 metabolite thought to be the result of oxidative metabolism, although these metabolites are poorly characterized. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following the oral administration of radiolabeled vericiguat, approximately 53% of the administered radioactivity was recovered in the urine and 45% in the feces. A human mass balance study found that the portion recovered in the urine comprised approximately 40.8% N-glucuronide metabolite, 7.7% other metabolites, and 9% unchanged parent drug, while virtually the entire portion recovered in the feces comprised unchanged vericiguat. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): In patients with heart failure, the half-life of vericiguat is 30 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Vericiguat is a low-clearance drug, with an observed plasma clearance of 1.6 L/h in healthy volunteers and 1.3 L/h in patients with systolic heart failure. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Data regarding overdosage with vericiguat are unavailable. Doses of up to 15mg once daily (50% greater than the recommended maintenance dose) have been studied and found to be well-tolerated. Symptoms of overdose are likely to be consistent with the adverse effect profile of vericiguat and may therefore involve significant hypotension for which symptomatic and supportive measures should be provided. Dialysis is unlikely to be of benefit in vericiguat overdose given its high degree of protein binding. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Verquvo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Zofenopril interact?

•Drug A: Abaloparatide •Drug B: Zofenopril •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Zofenopril. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •References: 1. Lee CH, Strosberg AM, Carver LA: Antihypertensive drugs: their postural hypotensive effect and their blood pressure lowering activity in conscious normotensive rats. Arch Int Pharmacodyn Ther. 1983 Jan;261(1):90-101. [https://go.drugbank.com/articles/A177104] •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abatacept and Abemaciclib interact?

•Drug A: Abatacept •Drug B: Abemaciclib •Severity: MAJOR •Description: The metabolism of Abemaciclib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •References: 1. Tamargo J, Le Heuzey JY, Mabo P: Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. Eur J Clin Pharmacol. 2015 May;71(5):549-67. doi: 10.1007/s00228-015-1832-0. Epub 2015 Apr 15. [https://go.drugbank.com/articles/A37372] 2. Blix HS, Viktil KK, Moger TA, Reikvam A: Drugs with narrow therapeutic index as indicators in the risk management of hospitalised patients. Pharm Pract (Granada). 2010 Jan;8(1):50-5. Epub 2010 Mar 15. [https://go.drugbank.com/articles/A38512] 3. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, Owen A: The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC. Br J Pharmacol. 2009 Feb;156(3):497-508. doi: 10.1111/j.1476-5381.2008.00050.x. Epub 2009 Jan 20. [https://go.drugbank.com/articles/A40066] 4. Morgan ET: Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos. 2001 Mar;29(3):207-12. [https://go.drugbank.com/articles/A40067] 5. Stavropoulou E, Pircalabioru GG, Bezirtzoglou E: The Role of Cytochromes P450 in Infection. Front Immunol. 2018 Jan 31;9:89. doi: 10.3389/fimmu.2018.00089. eCollection 2018. [https://go.drugbank.com/articles/A40068] •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. Inidicated as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In combination with fulvestrant, the progression-free survival for patients with HR-positive, HER2-negative breast cancer was 16.4 months compared to 9.3 months for patients taking a placebo with fulvestrant. As a monotherapy, 19.7% of patients taking abemaciclib achieved complete or partial shrinkage of their tumors for a median 8.6 months after treatment. Abemaciclib induces cell cycle arrest and exerts an antitumor activity in human tumor xenograft models. In patient investigations and a healthy volunteer study, abemaciclib is not shown to induce any clinically significant changes in the QTc interval. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Regulation of cell cycle is crucial in maintaining proper cell growth; dysregulated cell cycle signalling pathway is a key component in inducing hyperproliferation of cells and tumor formation in various cancers. G1 to S phase cell cycle progression, or transition through the G1 restriction point (R), is promoted by the retinoblastoma tumor suppressor protein (Rb)-mediated pathway. Activation of Rb-mediated pathway requires the interaction of Cyclin-dependent kinases (CDK) 4 and 6 with D-type cyclins, which drives the formation of active CDK4/CDK6 and subsequent phosphorylation of Rb. Rb is a tumor suppressant protein that inhibits proliferation through binding to and suppressing the activity of the E2F family of transcription factors. However, phosphorylation of Rb relieves suppression of E2F to allow expression of genes required for passage through the restriction point. This leads to increased expression of downstream signalling molecules and activity of protein kinases that promote the cell cycle progression and initiation of DNA replication. Phosphorylation of Rb and other proteins by CDK4/6 additionally leads to transcription of genes involved in cell cycle-independent activities including signal transduction, DNA repair transcriptional control, and mRNA processing. Abemaciclib selectively inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. Unlike other CDK inhibitors such as Palbociclib and Ribociclib, abemaciclib exhibits greater selectivity for CDK4 compared to CDK6. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The plasma concentration of the drug increases in a dose-proportional manner. Following a single oral dose administration of 200 mg abemaciclib, the mean peak plasma concentration (Cmax) of 158 ng/mL is reached after 6 hours. The median time to reach maximum plasma concentration (Tmax) ranges from 4-6 hours following an oral administration of abemaciclib over a range of 50–275 mg, but may range up to 24 hours. The absolute bioavailability of the drug is reported to be 45%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): According to in vitro models using animal brain tissues, the protein binding of abemaciclib is approximately 95-98%. While abemaciclib demonstrated in vitro binding to serum albumin, alpha-1-acid glycoprotein and other human plasma proteins in a concentration-depedent manner, its major metabolites are also shown to bind to plasms proteins as well. The approximate bound fractions of M2, M18 and M20 are 93.4%, 96.8% and 97.8%, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Abemaciclib mainly undergoes hepatic metabolism mediated by CYP3A4. The major metabolite formed is N-desethylabemaciclib (M2), while other metabolites hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1) are also formed. M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single oral dose of 150mg radiolabeled abemaciclib, approximately 81% of the total dose was recovered in feces while 3% of the dose was detected in urine. The majority of the drug is exceted as metabolites. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV). •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): According to the bacterial reverse mutation (Ames) assay, abemaciclib and its active metbolites M2 and M20 did not display mutagenic properties. Abemaciclib was not clastogenic in vitro rat bone marrow micronucleus assay. Repeat-dose toxicity studies were performed to assess the effects of abemaciclib in testis, epididymis, prostate, and seminal vesicle at doses ≥10 mg/kg/day in rats and ≥0.3 mg/kg/day in dogs which exceed the recommeded therapeutic doses in humans. The findings included decreased organ weights, intratubular cellular debris, hypospermia, tubular distillation, atrophy and degeneration or necrosis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Verzenio •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abatacept and Abrocitinib interact?

•Drug A: Abatacept •Drug B: Abrocitinib •Severity: MODERATE •Description: The metabolism of Abrocitinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •References: 1. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, Owen A: The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC. Br J Pharmacol. 2009 Feb;156(3):497-508. doi: 10.1111/j.1476-5381.2008.00050.x. Epub 2009 Jan 20. [https://go.drugbank.com/articles/A40066] 2. Morgan ET: Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos. 2001 Mar;29(3):207-12. [https://go.drugbank.com/articles/A40067] 3. Stavropoulou E, Pircalabioru GG, Bezirtzoglou E: The Role of Cytochromes P450 in Infection. Front Immunol. 2018 Jan 31;9:89. doi: 10.3389/fimmu.2018.00089. eCollection 2018. [https://go.drugbank.com/articles/A40068] •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Abrocitinib is indicated for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy. In the US, it is indicated to treat refractory, moderate-to-severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when the use of those therapies is inadvisable. Abrocitinib is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Abrocitinib mediates anti-inflammatory effects by blocking the signalling of pro-inflammatory cytokines implicated in atopic dermatitis. It dose-dependently reduces the serum markers of inflammation in atopic dermatitis, including high sensitivity C-reactive protein (hsCRP), interleukin-31 (IL-31), and thymus and activation regulated chemokine (TARC). These changes returned to near baseline within four weeks following drug discontinuation. At two weeks of treatment, the mean absolute lymphocyte count increased, which returned to baseline by nine months of treatment. Treatment with abrocitinib was associated with a dose-related increase in B cell counts and a dose-related decrease in NK cell counts: the clinical significance of these changes is unknown. Treatment with 200 mg abrocitinib once-daily was associated with a transient, dose-dependent decrease in platelet count with the nadir occurring at a median of 24 days. Recovery of platelet count (~40% recovery by 12 weeks) occurred without discontinuation of the treatment. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Janus kinases (JAKs) are a family consisting of four receptor-associated kinases - JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Upon ligand binding and subsequent dimerization of cytokine and hormone receptors, receptor-associated JAKs are activated and phosphorylated. This allows the binding of Signal Transducers and Activators of Transcription (STATs), which are transcription factors. STAT binds to the receptor, and JAK phosphorylates and activates STAT to create a STAT dimer. The STAT dimer translocates to the nucleus to upregulate the gene transcription of pro-inflammatory cytokines and growth factors implicated in atopic dermatitis. Blocking the JAK-STAT pathway is advantageous, as it is an intracellular signalling pathway where many pro-inflammatory pathways converge. Each JAK plays a role in the signalling and regulation of different cytokines and immune cells. In atopic dermatitis, JAK1 is the therapeutic target of focus as it is involved in the signalling of the γc family of cytokines involved in immune responses and disease pathophysiology, including IL-2, IL-4, IL-7, IL-9, and IL-15. Abrocitinib reversibly inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. Biochemical assays demonstrate that abrocitinib is selective for JAK1 over JAK2 (28-fold), JAK3 (>340-fold), and tyrosine kinase (TYK) 2 (43-fold), as well as the broader kinome. Similarly, in cellular settings, abrocitinib preferentially inhibited cytokine-induced STAT phosphorylation by signalling pairs involving JAK1, while sparing signalling by JAK2/JAK2, or JAK2/TYK2 pairs. The relevance of inhibition of specific JAK enzymes to the drug's therapeutic effectiveness is currently unknown. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Abrocitinib is absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. The peak plasma concentrations of abrocitinib are reached within one hour. Steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once-daily administration. Both C max and AUC of abrocitinib increased dose proportionally up to 200 mg. A high-fat meal, high-calorie meal increased AUC by 26% and C max by 29%, and prolongs T max by two hours; however, there are ultimately no clinically relevant effect on abrocitinib exposures. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): After intravenous administration, the volume of distribution of abrocitinib was approximately 100 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 64%, 37% and 29% of circulating abrocitinib and its active metabolites M1 and M2, respectively, are bound to plasma proteins. Abrocitinib and its active metabolites M1 and M2 bind predominantly to albumin and distribute equally between red blood cells and plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Abrocitinib undergoes CYP-mediated oxidative metabolism. CYP2C19 is the predominant enzyme, accounting for about 53% of drug metabolism. CYP2C9 is responsible for 30% of drug metabolism. About 11% and 6% of the drug is metabolized by CYP3A4 and CYP2B6, respectively. In a human radiolabeled study, the parent drug was the most prevalent circulating species. Polar mono-hydroxylated metabolites of abrocitinib - M1 (3-hydroxypropyl; PF-06471658), M2 (2-hydroxypropyl; PF-07055087), and M4 (pyrrolidinone pyrimidine; PF-07054874) - were also identified in the systemic circulation. M2 has a chiral center, thus has an enantiomer M3 (PF-07055090). At steady state, M2 and M4 are major metabolites and M1 is a minor metabolite. M2 has a pharmacological activity comparable to abrocitinib while M1 is less pharmacologically active than abrocitinib. M3 and M4 are inactive metabolites. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of the parent molecule (~60%) as well as M1 (~10%) and M2 (~30%) in the systemic circulation. The sum of unbound exposures of abrocitinib, M1 and M2, each expressed in molar units and adjusted for relative potencies, is referred to as the abrocitinib active moiety. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Abrocitinib is eliminated primarily by metabolic clearance mechanisms, with less than 1% of the dose being excreted in urine as an unchanged parent drug. The metabolites of abrocitinib are excreted predominantly in urine. Pharmacokinetics data up to and including a single oral dose of 800 mg in healthy adult volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 48 hours. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean elimination half-lives of abrocitinib and its two active metabolites, M1 and M2, range from three to five hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): There is no information available. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There is no experience regarding human overdosage with abrocitinib. In clinical trials, there were no specific toxicities observed when abrocitinib was administered in single oral doses of 800 mg and 400 mg daily for 28 days. An overdose should be responded with symptomatic and supportive treatment, as there is no specific antidote for overdose with abrocitinib. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abatacept and Acalabrutinib interact?

•Drug A: Abatacept •Drug B: Acalabrutinib •Severity: MAJOR •Description: The metabolism of Acalabrutinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •References: 1. Tamargo J, Le Heuzey JY, Mabo P: Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. Eur J Clin Pharmacol. 2015 May;71(5):549-67. doi: 10.1007/s00228-015-1832-0. Epub 2015 Apr 15. [https://go.drugbank.com/articles/A37372] 2. Blix HS, Viktil KK, Moger TA, Reikvam A: Drugs with narrow therapeutic index as indicators in the risk management of hospitalised patients. Pharm Pract (Granada). 2010 Jan;8(1):50-5. Epub 2010 Mar 15. [https://go.drugbank.com/articles/A38512] 3. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, Owen A: The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC. Br J Pharmacol. 2009 Feb;156(3):497-508. doi: 10.1111/j.1476-5381.2008.00050.x. Epub 2009 Jan 20. [https://go.drugbank.com/articles/A40066] 4. Morgan ET: Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos. 2001 Mar;29(3):207-12. [https://go.drugbank.com/articles/A40067] 5. Stavropoulou E, Pircalabioru GG, Bezirtzoglou E: The Role of Cytochromes P450 in Infection. Front Immunol. 2018 Jan 31;9:89. doi: 10.3389/fimmu.2018.00089. eCollection 2018. [https://go.drugbank.com/articles/A40068] •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Acalabrutinib is currently indicated for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. It has also been recently approved for chronic lymphocytic leukemia and small lymphocytic lymphoma. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Acalabrutinib is a Bruton Tyrosine Kinase inhibitor that prevents the proliferation, trafficking, chemotaxis, and adhesion of B cells. It is taken every 12 hours and can cause other effects such as atrial fibrillation, other malignancies, cytopenia, hemorrhage, and infection. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Mantle Cell Lymphoma (MCL) is a rare yet aggressive type of B-cell non-Hodgkin lymphoma (NHL) with poor prognosis. Subsequently, relapse is common in MCL patients and ultimately represents disease progression. Lymphoma occurs when immune system lymphocytes grow and multiply uncontrollably. Such cancerous lymphocytes may travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, and other organs where they can multiply and form a mass(es) called a tumor. One of the main kinds of lymphocytes that can develop into cancerous lymphomas are the body's own B-lymphocytes (B-cells). Bruton Tyrosine Kinase (BTK) is a signalling molecule of the B-cell antigen receptor and cytokine receptor pathways. Such BTK signaling causes the activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Acalabrutinib is a small molecule inhibitor of BTK. Both acalabrutinib and its active metabolite, ACP-5862, act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity. As a result, acalabrutinib inhibits BTK-mediated activation of downstream signaling proteins CD86 and CD69, which ultimately inhibits malignant B-cell proliferation and survival Whereas ibrutinib is typically recognized as the first-in-class BTK inhibitor, acalabrutinib is considered a second generation BTK inhibitor primarily because it demonstrates highter selectivity and inhibition of the targeted activity of BTK while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1. In effect, acalabrutinib was rationally designed to be more potent and selective than ibrutinib, all the while demonstrating fewer adverse effects - in theory - because of the drug's minimized off target effects. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The geometric mean absolute bioavailability of acalabrutinib is 25% with a median time to peak plasma concentrations (Tmax) of 0.75 hours. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean steady-state volume of distribution is approximately 34 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Reversible binding of acalabrutinib to human plasma protein is approximately 97.5%. The in vitro mean blood-to-plasma ratio is about 0.7. In vitro experiments at physiologic concentrations show that acalabrutinib can be 93.7% bound to human serum albumin and 41.1% bound to alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Acalabrutinib is mainly metabolized by CYP3A enzymes. ACP-5862 is identified to be the major active metabolite in plasma with a geometric mean exposure (AUC) that is about 2-3 times greater than the exposure of acalabrutinib. ACP-5862 is about 50% less potent than acalabrutinib in regards to the inhibition of BTK. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After administration of a single 100 mg radiolabelled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine. An irradiated dose of acalabrutinib was 34.7% recovered as the metabolite ACP-5862; 8.6% was recovered as unchanged acalabrutinub; 10.8 was recovered as a mixture of the M7, M8, M9, M10, and M11 metabolites; 5.9% was the M25 metabolite; 2.5% was recovered as the M3 metabolite. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): After administering a single oral dose of 100 mg acalabrutinib, the median terminal elimination half-life of the drug was found to be 0.9 (with a range of 0.6 to 2.8) hours. The half-life of the active metabolite, ACP-5862, is about 6.9 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Acalabrutinib's mean apparent oral clearance (CL/F) is observed to be 159 L/hr with similar PK between patients and healthy subjects, based on population PK analysis. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Data regarding the toxicity of acalabrutinib is not readily available. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Calquence •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abatacept and Acebutolol interact?

•Drug A: Abatacept •Drug B: Acebutolol •Severity: MODERATE •Description: The metabolism of Acebutolol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •References: 1. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, Owen A: The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC. Br J Pharmacol. 2009 Feb;156(3):497-508. doi: 10.1111/j.1476-5381.2008.00050.x. Epub 2009 Jan 20. [https://go.drugbank.com/articles/A40066] 2. Morgan ET: Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos. 2001 Mar;29(3):207-12. [https://go.drugbank.com/articles/A40067] 3. Stavropoulou E, Pircalabioru GG, Bezirtzoglou E: The Role of Cytochromes P450 in Infection. Front Immunol. 2018 Jan 31;9:89. doi: 10.3389/fimmu.2018.00089. eCollection 2018. [https://go.drugbank.com/articles/A40068] •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the management of hypertension and ventricular premature beats in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Acebutolol is a cardioselective, beta-adrenoreceptor blocking agent, which possesses mild intrinsic sympathomimetic activity (ISA) in its therapeutically effective dose range. In general, beta-blockers reduce the work the heart has to do and allow it to beat more regularly. Acebutolol has less antagonistic effects on peripheral vascular ß2-receptors at rest and after epinephrine stimulation than nonselective beta-antagonists. Low doses of acebutolol produce less evidence of bronchoconstriction than nonselective agents like propranolol but more than atenolol. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Acebutolol is a selective β1-receptor antagonist. Activation of β1-receptors by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Acebutolol blocks these receptors, lowering the heart rate and blood pressure. This drug then has the reverse effect of epinephrine. In addition, beta blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Well absorbed from the Gl tract with an absolute bioavailability of approximately 40% for the parent compound. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 26% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Subject to extensive first-pass hepatic biotransformation (primarily to diacetolol). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Elimination via renal excretion is approximately 30% to 40% and by non-renal mechanisms 50% to 60%, which includes excretion into the bile and direct passage through the intestinal wall. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The plasma elimination half-life is approximately 3 to 4 hours. The half-life of its metabolite, diacetolol, is 8 to 13 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose include extreme bradycardia, advanced atrioventricular block, intraventricular conduction defects, hypotension, severe congestive heart failure, seizures, and in susceptible patients, bronchospasm, and hypoglycemia. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Sectral •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (±)-acebutolol 3'-acetyl-4'-(2-hydroxy-3-(isopropylamino)propoxy)butyranilide 5'-butyramido-2'-(2-hydroxy-3-isopropylaminopropoxy)acetophenone Acebutolol (common) Acebutololum (common) Acetobutolol (common) N-(3-acetyl-4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl)butanamide N-[3-acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl]butanamide

Do Abatacept and Acenocoumarol interact?

•Drug A: Abatacept •Drug B: Acenocoumarol •Severity: MAJOR •Description: The metabolism of Acenocoumarol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •References: 1. Tamargo J, Le Heuzey JY, Mabo P: Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. Eur J Clin Pharmacol. 2015 May;71(5):549-67. doi: 10.1007/s00228-015-1832-0. Epub 2015 Apr 15. [https://go.drugbank.com/articles/A37372] 2. Blix HS, Viktil KK, Moger TA, Reikvam A: Drugs with narrow therapeutic index as indicators in the risk management of hospitalised patients. Pharm Pract (Granada). 2010 Jan;8(1):50-5. Epub 2010 Mar 15. [https://go.drugbank.com/articles/A38512] 3. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, Owen A: The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC. Br J Pharmacol. 2009 Feb;156(3):497-508. doi: 10.1111/j.1476-5381.2008.00050.x. Epub 2009 Jan 20. [https://go.drugbank.com/articles/A40066] 4. Morgan ET: Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos. 2001 Mar;29(3):207-12. [https://go.drugbank.com/articles/A40067] 5. Stavropoulou E, Pircalabioru GG, Bezirtzoglou E: The Role of Cytochromes P450 in Infection. Front Immunol. 2018 Jan 31;9:89. doi: 10.3389/fimmu.2018.00089. eCollection 2018. [https://go.drugbank.com/articles/A40068] •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment and prevention of thromboembolic diseases. More specifically, it is indicated for the prevention of cerebral embolism, deep vein thrombosis, pulmonary embolism, thromboembolism in infarction and transient ischemic attacks. It is used for the treatment of deep vein thrombosis and myocardial infarction. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Acenocoumarol inhibits the reduction of vitamin K by vitamin K reductase. This prevents carboxylation of certain glutamic acid residues near the N-terminals of clotting factors II, VII, IX and X, the vitamin K-dependent clotting factors. Glutamic acid carboxylation is important for the interaction between these clotting factors and calcium. Without this interaction, clotting cannot occur. Both the extrinsic (via factors VII, X and II) and intrinsic (via factors IX, X and II) are affected by acenocoumarol. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Acenocoumarol inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent clotting factors, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited resulting in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly absorbed orally with greater than 60% bioavailability. Peak plasma levels are attained 1 to 3 hours following oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution at steady-state appeared to be significantly dose dependent: 78 ml/kg for doses < or = 20 microg/kg and 88 ml/kg for doses > 20 microg/kg respectively •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 98.7% protein bound, mainly to albumin •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Extensively metabolized in the liver via oxidation forming two hydroxy metabolites and keto reduction producing two alcohol metabolites. Reduction of the nitro group produces an amino metabolite which is further transformed to an acetoamido metabolite. Metabolites do not appear to be pharmacologically active. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Mostly via the kidney as metabolites •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 8 to 11 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The onset and severity of the symptoms are dependent on the individual's sensitivity to oral anticoagulants, the severity of the overdosage, and the duration of treatment. Bleeding is the major sign of toxicity with oral anticoagulant drugs. The most frequent symptoms observed are: cutaneous bleeding (80%), haematuria (with renal colic) (52%), haematomas, gastrointestinal bleeding, haematemesis, uterine bleeding, epistaxis, gingival bleeding and bleeding into the joints. Further symptoms include tachycardia, hypotension, peripheral circulatory disorders due to loss of blood, nausea, vomiting, diarrhoea and abdominal pains. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3-(alpha-(4'-Nitrophenyl)-beta-acetylethyl)-4-hydroxycoumarin 3-(alpha-(p-Nitrophenol)-beta-acetylethyl)-4-hydroxycoumarin 3-(alpha-Acetonyl-4-nitrobenzyl)-4-hydroxycoumarin 3-(alpha-Acetonyl-p-nitrobenzyl)-4-hydroxycoumarin 3-(alpha-p-Nitrophenyl-beta-acetylethyl)-4-hydroxycoumarin 4-Hydroxy-3-(1-(4-nitrophenyl)-3-oxobutyl)-2H-1-benzopyran-2-one 4-Hydroxy-3-[1-(4-nitrophenyl)-3-oxobutyl]-2H-chromen-2-one Acenocoumarin (common) Acénocoumarol (common) Acenocoumarol (common) Acenocoumarolum (common) Acenocumarol (common) Acenocumarolo (common) Acenokumarin (common) Nicoumalone (common) Nicumalon (common) Nitrophenylacetylethyl-4-hydroxycoumarine Nitrovarfarian (common) Nitrowarfarin (common)

Do Abatacept and Acetaminophen interact?

•Drug A: Abatacept •Drug B: Acetaminophen •Severity: MODERATE •Description: The metabolism of Acetaminophen can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •References: 1. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, Owen A: The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC. Br J Pharmacol. 2009 Feb;156(3):497-508. doi: 10.1111/j.1476-5381.2008.00050.x. Epub 2009 Jan 20. [https://go.drugbank.com/articles/A40066] 2. Morgan ET: Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos. 2001 Mar;29(3):207-12. [https://go.drugbank.com/articles/A40067] 3. Stavropoulou E, Pircalabioru GG, Bezirtzoglou E: The Role of Cytochromes P450 in Infection. Front Immunol. 2018 Jan 31;9:89. doi: 10.3389/fimmu.2018.00089. eCollection 2018. [https://go.drugbank.com/articles/A40068] •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): In general, acetaminophen is used for the treatment of mild to moderate pain and reduction of fever. It is available over the counter in various forms, the most common being oral forms. Acetaminophen injection is indicated for the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the reduction of fever. Because of its low risk of causing allergic reactions, this drug can be administered in patients who are intolerant to salicylates and those with allergic tendencies, including bronchial asthmatics. Specific dosing guidelines should be followed when administering acetaminophen to children. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Animal and clinical studies have determined that acetaminophen has both antipyretic and analgesic effects. This drug has been shown to lack anti-inflammatory effects. As opposed to the salicylate drug class, acetaminophen does not disrupt tubular secretion of uric acid and does not affect acid-base balance if taken at the recommended doses. Acetaminophen does not disrupt hemostasis and does not have inhibitory activities against platelet aggregation. Allergic reactions are rare occurrences following acetaminophen use. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): According to its FDA labeling, acetaminophen's exact mechanism of action has not been fully established - despite this, it is often categorized alongside NSAIDs (nonsteroidal anti-inflammatory drugs) due to its ability to inhibit the cyclooxygenase (COX) pathways. It is thought to exert central actions which ultimately lead to the alleviation of pain symptoms. One theory is that acetaminophen increases the pain threshold by inhibiting two isoforms of cyclooxygenase, COX-1 and COX-2, which are involved in prostaglandin (PG) synthesis. Prostaglandins are responsible for eliciting pain sensations. Acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, therefore, has no peripheral anti-inflammatory effects. Though acetylsalicylic acid (aspirin) is an irreversible inhibitor of COX and directly blocks the active site of this enzyme, studies have shown that acetaminophen (paracetamol) blocks COX indirectly. Studies also suggest that acetaminophen selectively blocks a variant type of the COX enzyme that is unique from the known variants COX-1 and COX-2. This enzyme has been referred to as COX-3. The antipyretic actions of acetaminophen are likely attributed to direct action on heat-regulating centers in the brain, resulting in peripheral vasodilation, sweating, and loss of body heat. The exact mechanism of action of this drug is not fully understood at this time, but future research may contribute to deeper knowledge. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Acetaminophen has 88% oral bioavailability and reaches its highest plasma concentration 90 minutes after ingestion. Peak blood levels of free acetaminophen are not reached until 3 hours after rectal administration of the suppository form of acetaminophen and the peak blood concentration is approximately 50% of the observed concentration after the ingestion of an equivalent oral dose (10-20 mcg/mL). The percentage of a systemically absorbed rectal dose of acetaminophen is inconsistent, demonstrated by major differences in the bioavailability of acetaminophen after a dose administered rectally. Higher rectal doses or an increased frequency of administration may be used to attain blood concentrations of acetaminophen similar to those attained after oral acetaminophen administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Volume of distribution is about 0.9L/kg. 10 to 20% of the drug is bound to red blood cells. Acetaminophen appears to be widely distributed throughout most body tissues except in fat. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The binding of acetaminophen to plasma proteins is low (ranging from 10% to 25%), when given at therapeutic doses. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Acetaminophen is the major metabolite of phenacetin and acetanilid. Acetaminophen is mainly metabolized in the liver by first-order kinetics and its metabolism of comprised of 3 pathways: conjugation with glucuronide, conjugation with sulfate, and oxidation through the cytochrome P450 enzyme pathway, mainly CYP2E1, to produce a reactive metabolite (N-acetyl-p-benzoquinone imine or NAPQI). At normal therapeutic doses, NAPQI undergoes fast conjugation with glutathione and is subsequently metabolized to produce both cysteine and mercapturic acid conjugates. High doses of acetaminophen (overdoses) can lead to hepatic necrosis due to the depletion of glutathione and of binding of high levels of reactive metabolite (NAPQI) to important parts of liver cells. The abovementioned damage to the liver can be prevented by the early administration of sulfhydryl compounds, for example, methionine and N-acetylcysteine. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Acetaminophen metabolites are mainly excreted in the urine. Less than 5% is excreted in the urine as free (unconjugated) acetaminophen and at least 90% of the administered dose is excreted within 24 hours. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life for adults is 2.5 h after an intravenous dose of 15 mg/kg. After an overdose, the half-life can range from 4 to 8 hours depending on the severity of injury to the liver, as it heavily metabolizes acetaminophen. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Adults: 0.27 L/h/kg following a 15 mg/kg intravenous (IV) dose. Children: 0.34 L/h/kg following a 15 mg/kg intravenous (IV dose). •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50 = 338 mg/kg (oral, mouse); LD50 = 1944 mg/kg (oral, rat) Overdose and liver toxicity Acetaminophen overdose may be manifested by renal tubular necrosis, hypoglycemic coma, and thrombocytopenia. Sometimes, liver necrosis can occur as well as liver failure. Death and the requirement of a liver transplant may also occur. Metabolism by the CYP2E1 pathway releases a toxic acetaminophen metabolite known as N-acetyl-p-benzoquinoneimine (NAPQI). The toxic effects caused by this drug are attributed to NAPQI, not acetaminophen alone. Carcinogenesis Long-term studies in mice and rats have been completed by the National Toxicology Program to study the carcinogenic risk of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice consumed a diet containing acetaminophen up to 6,000 ppm. Female rats showed evidence of carcinogenic activity demonstrated by a higher incidence of mononuclear cell leukemia at doses 0.8 times the maximum human daily dose (MHDD). No evidence of carcinogenesis in male rats (0.7 times) or mice (1.2 to 1.4 times the MHDD) was noted. The clinical relevance of this finding in humans is unknown. Mutagenesis Acetaminophen was not found to be mutagenic in the bacterial reverse mutation assay (Ames test). Despite this finding, acetaminophen tested positive in the in vitro mouse lymphoma assay as well as the in vitro chromosomal aberration assay using human lymphocytes. In published studies, acetaminophen has been reported to be clastogenic (disrupting chromosomes) when given a high dose of 1,500 mg/kg/day to the rat model (3.6 times the MHDD). No clastogenicity was observed at a dose of 750 mg/kg/day (1.8 times the MHDD), indicating that this drug has a threshold before it may cause mutagenesis. The clinical relevance of this finding in humans is unknown. Impairment of Fertility In studies conducted by the National Toxicology Program, fertility assessments have been performed in Swiss mice in a continuous breeding study. No effects on fertility were seen. Use in pregnancy and nursing The FDA label for acetaminophen considers it a pregnancy category C drug, meaning this drug has demonstrated adverse effects in animal studies. No human clinical studies in pregnancy have been done to this date for intravenous acetaminophen. Use acetaminophen only when necessary during pregnancy. Epidemiological data on oral acetaminophen use in pregnant women demonstrate no increase in the risk of major congenital malformations. While prospective clinical studies examining the results of nursing with acetaminophen use have not been conducted, acetaminophen is found secreted in human milk at low concentrations after oral administration. Data from more than 15 nursing mothers taking acetaminophen was obtained, and the calculated daily dose of acetaminophen that reaches the infant is about 1 to 2% of the maternal dose. Caution should be observed when acetaminophen is taken by a nursing woman. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Acephen, Acetadryl, Allzital, Apadaz, Arthriten Inflammatory Pain, Bupap, Butapap, Cetafen, Children's Silapap, Combogesic, Coricidin Hbp Cold & Flu, Darvocet-N, Dayquil Sinex, Diphen, Dolofin, Dologen, Dologesic Reformulated Jun 2016, Duralgina, Dvorah, Endocet, Esgic, Exaprin, Excedrin, Excedrin PM Triple Action, Excedrin Tension Headache, Feverall, Fioricet, Fioricet With Codeine, Goody's Back & Body Pain Relief, Goody's Body Pain, Goody's Extra Strength, Goody's Headache Relief Shot, Goody's PM, Hycet, Legatrin PM, Little Fevers, Lorcet, Lortab, Mapap, Mersyndol, Midol Complete, Midol Cramps & Bodyaches, Nalocet, Norco, Orbivan, Pamprin Max Formula, Pamprin Multi-symptom, Panadol, Pediacare Children's Fever Reducer Pain Reliever, Percocet, Percogesic Reformulated Jan 2011, Pharbetol, Premsyn Pms, Prolate, Rivacocet, Robaxacet, Robaxacet-8, Roxicet, Sudafed PE Sinus Headache, Tactinal, Tencon, Trezix, Triatec, Triatec-30, Triatec-8, Tylenol, Tylenol PM, Tylenol With Codeine, Ultracet, Vanatol, Vanatol S, Vanquish, Xodol, Xolox, Zamicet, Zflex, Zydone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 4-(Acetylamino)phenol 4-acetamidophenol 4'-hydroxyacetanilide Acenol (common) Acetaminofén (common) Acetaminophen (common) Acétaminophène (common) APAP (common) N-acetyl-p-aminophenol p-acetamidophenol p-acetaminophenol p-Acetylaminophenol p-hydroxy-acetanilid p-hydroxyacetanilide p-hydroxyphenolacetamide Paracetamol (common) Paracétamol (common) Paracetamolum (common)

Do Abatacept and Acetylsalicylic acid interact?

•Drug A: Abatacept •Drug B: Acetylsalicylic acid •Severity: MODERATE •Description: The metabolism of Acetylsalicylic acid can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •References: 1. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, Owen A: The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC. Br J Pharmacol. 2009 Feb;156(3):497-508. doi: 10.1111/j.1476-5381.2008.00050.x. Epub 2009 Jan 20. [https://go.drugbank.com/articles/A40066] 2. Morgan ET: Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos. 2001 Mar;29(3):207-12. [https://go.drugbank.com/articles/A40067] 3. Stavropoulou E, Pircalabioru GG, Bezirtzoglou E: The Role of Cytochromes P450 in Infection. Front Immunol. 2018 Jan 31;9:89. doi: 10.3389/fimmu.2018.00089. eCollection 2018. [https://go.drugbank.com/articles/A40068] •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed

Do Abatacept and Acyclovir interact?

•Drug A: Abatacept •Drug B: Acyclovir •Severity: MODERATE •Description: The metabolism of Acyclovir can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •References: 1. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, Owen A: The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC. Br J Pharmacol. 2009 Feb;156(3):497-508. doi: 10.1111/j.1476-5381.2008.00050.x. Epub 2009 Jan 20. [https://go.drugbank.com/articles/A40066] 2. Morgan ET: Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos. 2001 Mar;29(3):207-12. [https://go.drugbank.com/articles/A40067] 3. Stavropoulou E, Pircalabioru GG, Bezirtzoglou E: The Role of Cytochromes P450 in Infection. Front Immunol. 2018 Jan 31;9:89. doi: 10.3389/fimmu.2018.00089. eCollection 2018. [https://go.drugbank.com/articles/A40068] •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): An acyclovir topical cream is indicated to treat recurrent herpes labialis in immunocompetent patients 12 years and older. Acyclovir oral tablets, capsules, and suspensions are indicated to treat herpes zoster, genital herpes, and chickenpox. An acyclovir topical ointment is indicated to treat initial genital herpes and limited non-life-threatening mucocutaneous herpes simplex in immunocompromised patients. An acyclovir cream with hydrocortisone is indicated to treat recurrent herpes labialis, and shortening lesion healing time in patients 6 years and older. An acyclovir buccal tablet is indicated for the treatment of recurrent herpes labialis. An acyclovir ophthalmic ointment is indicated to treat acute herpetic keratitis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Acyclovir is a nucleoside analog that inhibits the action of viral DNA polymerase and DNA replication of different herpesvirus. Acyclovir has a wide therapeutic window as overdose is rare in otherwise healthy patients. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Acyclovir is becomes acyclovir monophosphate due to the action of viral thymidine kinase. Acyclovir monophosphate is converted to the diphosphate form by guanylate kinase. Acyclovir diphosphate is converted to acyclovir triphosphate by nucleoside diphosphate kinase, pyruvate kinase, creatine kinase, phosphoglycerate kinase, succinyl-CoA synthetase, phosphoenolpyruvate carboxykinase and adenylosuccinate synthetase. Acyclovir triphosphate has higher affinity for viral DNA polymerase than cellular DNA polymerase and incorporates into the DNA where the missing 2' and 3' carbons causes DNA chain termination. In other cases acyclovir triphosphate competes so strongly for viral DNA polymerase that other bases cannot associate with the enzyme, inactivating it. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The oral bioavailability of acyclovir is 10-20% but decreases with increasing doses. Acyclovir ointment is <0.02-9.4% absorbed. Acyclovir buccal tablets and ophthalmic ointment are minimally absorbed. The bioavailability of acyclovir is not affected by food. Acyclovir has a mean T max of 1.1±0.4 hours, mean C max of 593.7-656.5ng/mL, and mean AUC of 2956.6-3102.5h/*ng/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of acyclovir is 0.6L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Acyclovir is 9-33% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Acyclovir is <15% oxidized to 9-carboxymethoxymethylguanine by alcohol dehydrogenase and aldehyde dehydrogenase and 1% 8-hydroxylated to 8-hydroxy-acyclovir by aldehyde oxidase. Acyclovir is becomes acyclovir monophosphate due to the action of viral thymidine kinase. Acyclovir monophosphate is converted to the diphosphate form by guanylate kinase. Acyclovir diphosphate is converted to acyclovir triphosphate by nucleoside diphosphate kinase, pyruvate kinase, creatine kinase, phosphoglycerate kinase, succinyl-CoA synthetase, phosphoenolpyruvate carboxykinase and adenylosuccinate synthetase. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The majority of acyclovir is excreted in the urine as unchanged drug. 90-92% of the drug can be excreted unchanged through glomerular filtration and tubular secretion. <2% of the drug is recovered in feces and <0.1% is expired as CO 2. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The clearance of acyclovir varies from 2.5-3 hours depending on the creatinine clearance of the patient. The plasma half life of acyclovir during hemodialysis is approximately 5 hours. The mean half life in patients from 7 months to 7 years old is 2.6 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The renal clearance of acyclovir is 248mL/min/1.73m. The total clearance in neonates if 105-122mL/min/1.73m. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose include agitation, coma, seizures, lethargy, and precipitation in renal tubules. These symptoms are more common in patients given high doses without monitoring of fluid and electrolyte balance or reduced kidney function. In the case of an overdose, treat with symptomatic and supportive care. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Sitavig, Xerese, Zovirax •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abatacept and Adalimumab interact?

•Drug A: Abatacept •Drug B: Adalimumab •Severity: MODERATE •Description: The risk or severity of infection can be increased when Adalimumab is combined with Abatacept. •Extended Description: Since adalimumab and abatacept are both immunosuppressants, co-administration of adalimumab and abatacept can increase the risk of infection. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abatacept and Agomelatine interact?

•Drug A: Abatacept •Drug B: Agomelatine •Severity: MODERATE •Description: The metabolism of Agomelatine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •References: 1. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, Owen A: The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC. Br J Pharmacol. 2009 Feb;156(3):497-508. doi: 10.1111/j.1476-5381.2008.00050.x. Epub 2009 Jan 20. [https://go.drugbank.com/articles/A40066] 2. Morgan ET: Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos. 2001 Mar;29(3):207-12. [https://go.drugbank.com/articles/A40067] 3. Stavropoulou E, Pircalabioru GG, Bezirtzoglou E: The Role of Cytochromes P450 in Infection. Front Immunol. 2018 Jan 31;9:89. doi: 10.3389/fimmu.2018.00089. eCollection 2018. [https://go.drugbank.com/articles/A40068] •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Agomelatine is indicated to treat major depressive episodes in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Agomelatine resynchronises circadian rhythms in animal models of delayed sleep phase syndrome and other circadian rhythm disruptions. It increases noradrenaline and dopamine release specifically in the frontal cortex and has no influence on the extracellular levels of serotonin. Agomelatine has shown an antidepressant-like effect in animal depression models, (learned helplessness test, despair test, and chronic mild stress) circadian rhythm desynchronisation, and in stress and anxiety models. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset. Controlled studies in humans have shown that agomelatine is as effective as the SSRI antidepressants paroxetine and sertraline in the treatment of major depression •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The novel antidepressant agent, agomelatine, behaves as an agonist at melatonin receptors (MT1 and MT2) and as an antagonist at serotonin (5-HT)(2C) receptors. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Bioavailability is less than 5%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): > 95% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic (90% CYP1A2 and 10% CYP2C9). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): <2 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Valdoxan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abatacept and Albendazole interact?

•Drug A: Abatacept •Drug B: Albendazole •Severity: MODERATE •Description: The metabolism of Albendazole can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •References: 1. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, Owen A: The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC. Br J Pharmacol. 2009 Feb;156(3):497-508. doi: 10.1111/j.1476-5381.2008.00050.x. Epub 2009 Jan 20. [https://go.drugbank.com/articles/A40066] 2. Morgan ET: Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos. 2001 Mar;29(3):207-12. [https://go.drugbank.com/articles/A40067] 3. Stavropoulou E, Pircalabioru GG, Bezirtzoglou E: The Role of Cytochromes P450 in Infection. Front Immunol. 2018 Jan 31;9:89. doi: 10.3389/fimmu.2018.00089. eCollection 2018. [https://go.drugbank.com/articles/A40068] •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of parenchymal neurocysticercosis due to active lesions caused by larval forms of the pork tapeworm, Taenia solium and for the treatment of cystic hydatid disease of the liver, lung, and peritoneum, caused by the larval form of the dog tapeworm, Echinococcus granulosus. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Albendazole is a broad-spectrum anthelmintic. The principal mode of action for albendazole is by its inhibitory effect on tubulin polymerization which results in the loss of cytoplasmic microtubules. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Albendazole causes degenerative alterations in the tegument and intestinal cells of the worm by diminishing its energy production, ultimately leading to immobilization and death of the parasite. It works by binding to the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or assembly into microtubules. As cytoplasmic microtubules are critical in promoting glucose uptake in larval and adult stages of the susceptible parasites, the glycogen stores of the parasites are depleted. Degenerative changes in the endoplasmic reticulum, the mitochondria of the germinal layer, and the subsequent release of lysosomes result in decreased production of adenosine triphosphate (ATP), which is the energy required for the survival of the helminth. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Poorly absorbed from the gastrointestinal tract due to its low aqueous solubility. Oral bioavailability appears to be enhanced when coadministered with a fatty meal (estimated fat content 40 g) •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 70% bound to plasma protein •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Rapidly converted in the liver to the primary metabolite, albendazole sulfoxide, which is further metabolized to albendazole sulfone and other primary oxidative metabolites that have been identified in human urine. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Albendazole is rapidly converted in the liver to the primary metabolite, albendazole sulfoxide, which is further metabolized to albendazole sulfone and other primary oxidative metabolites that have been identified in human urine. Urinary excretion of albendazole sulfoxide is a minor elimination pathway with less than 1% of the dose recovered in the urine. Biliary elimination presumably accounts for a portion of the elimination as evidenced by biliary concentrations of albendazole sulfoxide similar to those achieved in plasma. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Terminal elimination half-life ranges from 8 to 12 hours (single dose, 400mg). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose include elevated liver enzymes, headaches, hair loss, low levels of white blood cells (neutropenia), fever, and itching. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Albenza •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (5-(propylthio)-1H-benzimidazol-2-yl)carbamic acid methyl ester 5-(propylthio)-2-carbomethoxyaminobenzimidazole Albendazol (common) Albendazole (common) Albendazolum (common) Eskazole (common) O-methyl N-(5-(propylthio)-2-benzimidazolyl)carbamate Proftril (common)