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Do Abaloparatide and Acebutolol interact?

•Drug A: Abaloparatide •Drug B: Acebutolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Acebutolol 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 hypertension and ventricular premature beats 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): 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): 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): 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): 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 Gl tract with an absolute bioavailability of approximately 40% for the parent compound. •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): 26% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Subject to extensive first-pass hepatic biotransformation (primarily to diacetolol). •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •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): The mean half-life of abaloparatide is approximately one hour. •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): 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 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): Tymlos •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 Abaloparatide and Aldesleukin interact?

•Drug A: Abaloparatide •Drug B: Aldesleukin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Aldesleukin 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 treatment of adults with metastatic renal cell carcinoma. •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): Used to treat renal cell carcinoma, Aldesleukin induces the enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines, the enhancement of lymphocyte cytotoxicity, the induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and the induction of interferon-gamma production. IL-2 is normally produced by the body, secreted by T cells, and stimulates growth and differentiation of T cell response. It can be used in immunotherapy to treat cancer. It enhances the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor. •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): Aldesleukin binds to the IL-2 receptor which leads to heterodimerization of the cytoplasmic domains of the IL-2R beta and gamma(c) chains, activation of the tyrosine kinase Jak3, and phosphorylation of tyrosine residues on the IL-2R beta chain. These events led to the creation of an activated receptor complex, to which various cytoplasmic signaling molecules are recruited and become substrates for regulatory enzymes (especially tyrosine kinases) that are associated with the receptor. These events stimulate growth and differentiation of T cells. •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): 0.18 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): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The pharmacokinetic profile of Proleukin is characterized by high plasma concentrations following a short IV infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. Following the initial rapid organ distribution, the primary route of clearance of circulating proleukin is the kidney. Greater than 80% of the amount of Proleukin distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 13 min-85 min •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): Proleukin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Aliskiren interact?

•Drug A: Abaloparatide •Drug B: Aliskiren •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Aliskiren. •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): Aliskiren is used for the treatment of hypertension in children above 6 years and adults. This drug may also be used in conjunction with antihypertensives such as calcium channel blockers and thiazides in products form to provide additional blood pressure control. •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): Aliskiren reduces blood pressure by inhibiting renin. This leads to a cascade of events that decreases blood pressure, lowering the risk of fatal and nonfatal cardiovascular events including stroke 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): Aliskiren is a renin inhibitor. Renin is secreted by the kidneys when blood volume and renal perfusion decrease. It normally cleaves the protein angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II, an active protein. Angiotensin II is a potent vasoconstrictor that causes the release of catecholamines into the circulation. It also promotes the secretion of aldosterone in addition to sodium reabsorption, increasing blood pressure. Additionally, angiotensin II acts on the adrenal cortex where it stimulates aldosterone release. Aldosterone increases sodium reabsorption and potassium excretion in the nephron. Aliskiren prevents the above process via binding to renin at its active site, stopping the cleavage of angiotensin, in turn inhibiting the formation of angiotensin I. This ends the cascade of angiotensin II mediated mechanisms that normally 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): Aliskiren is absorbed in the gastrointestinal tract and is poorly absorbed with a bioavailability between 2.0 and 2.5%. Peak plasma concentrations of aliskiren are achieved between 1 to 3 hours after administration. Steady-state concentrations of aliskiren are achieved within 7-8 days of regular administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Unchanged aliskiren accounts for about 80% of the drug found in the plasma. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The plasma protein binding of aliskiren ranges from 47-51%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): About 80% of the drug in plasma following oral administration is unchanged. Two major metabolites account for about 1-3% of aliskiren in the plasma. One metabolite is an O-demethylated alcohol derivative and the other is a carboxylic acid derivative. Minor oxidized and hydrolyzed metabolites may also be found in the plasma. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Aliskiren is mainly excreted via the hepatobiliary route and by oxidative metabolism by hepatic cytochrome enzymes. Approximately one-quarter of the absorbed dose appears in the urine as unchanged parent drug. One pharmacokinetic study of radiolabeled aliskiren detected 0.6% radioactivity in the urine and more than 80% in the feces, suggesting that aliskiren is mainly eliminated by the fecal route. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Plasma half-life for aliskiren can range from 30 to 40 hours with an accumulation half-life of about 24 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Aliskiren is partially cleared in the kidneys, and safety data have not been established for patients with a creatinine clearance of less than 30 mL/min. One pharmacokinetic study revealed an average renal clearance of 1280 +/- 500 mL/hour 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 of aliskiren in rats is >2000 mg/kg. Overdose information is limited in the literature, however, an overdose with aliskiren is likely to result in hypotension. Supportive treatment should be initiated in the case of an overdose. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Rasilez, Tekturna, Tekturna Hct •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Ambrisentan interact?

•Drug A: Abaloparatide •Drug B: Ambrisentan •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Ambrisentan. •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): Ambrisentan is indicated for treatment of idiopathic (‘primary’) pulmonary arterial hypertension (IPAH) and pulmonary arterial hypertension (PAH) associated with connective tissue disease in patients with WHO functional class II or III symptoms. In the United States of America, ambrisentan is also indicated in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. •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): Ambrisentan 10 mg daily had no significant effect on the QTc interval, whereas a 40 mg daily dose of ambrisentan increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. Significant QTc prolongation is not expected in patients taking ambrisentan without concomitant metabolic inhibitors. Plasma concentrations of B-type natriuretic peptide (BNP) in patients who received ambrisentan for 12 weeks were significantly decreased. Two Phase III placebo-controlled studies demonstrated a decrease in BNP plasma concentrations by 29% in the 2.5 mg group, 30% in the 5 mg group, and 45% in the 10 mg group (p < 0.001 for each dose group) and an increase by 11% in the placebo group. •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): Endothelin-1 (ET-1) is an endogenous peptide that acts on the endothelin type A (ETA) and endothelin type B (ETB) receptors in vascular smooth muscle and endothelium. ETA-mediated actions include vasoconstriction and cell proliferation, whereas ETB predominantly mediates vasodilation, anti-proliferation, and ET-1 clearance. In patients with pulmonary arterial hypertension, ET-1 levels are increased and correlate with increased right arterial pressure and severity of disease. Ambrisentan is one of several newly developed vasodilator drugs that selectively target the endothelin type A (ETA) receptor, inhibiting its action and preventing vasoconstriction. Selective inhibition of the ETA receptor prevents phospholipase C-mediated vasoconstriction and protein kinase C-mediated cell proliferation. Endothelin type B (ETB) receptor function is not significantly inhibited, and nitric oxide and prostacyclin production, cyclic GMP- and cyclic AMP-mediated vasodilation, and endothelin-1 (ET-1) clearance is preserved. •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): Ambrisentan is rapidly absorbed with peak plasma concentrations occuring around 2 hours after oral administration. Cmax and AUC increase proportionally with dose across the therapeutic dosing range. Absolute oral bioavailability of ambrisentan is unknown. Absorption is not affected by food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Ambrisentan has a low distribution into red blow cells, with a mean blood:plasma ratio of 0.57 and 0.61 in males and females, respectively. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Ambrisentan is 99% plasma protein bound, primarily to albumin (96.5%) and to a lesser degree alpha1-acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Ambrisentan is a metabolized primarily by uridine 5’-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S,1A3S to form ambrisentan glucuronide. Ambrisentan is also metabolized to a lesser extent by CYP3A4, CYP3A5 and CYP2C19 to form 4- hydroxymethyl ambrisentan which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Ambrisentan is primarily cleared by non-renal pathways. Along with its metabolites, ambrisentan is primarily found in the feces following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Ambrisentan has a terminal half-life of 15 hours. It is thought that steady state is achieved after around 4 days of repeat-dosing. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The mean oral clearance of ambrisentan was found to be 38 mL/min in healthy subjects and 19 mL/min in patients with pulmonary artery hypertension. •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): Ambrisentan is teratogenic and has a high risk of embryo-fetal toxicity. LD50 was found to be greater than or equal to 3160 mg/kg when studied in rats. There was no evidence of carcinogenic potential in 2 year oral daily dosing studies in rats and mice. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Letairis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy- 3,3-diphenylpropanoic acid Ambrisentan (common)

Do Abaloparatide and Amifostine interact?

•Drug A: Abaloparatide •Drug B: Amifostine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amifostine 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 reduction in the cumulative renal toxicity in patients with ovarian cancer (using cisplatin) and moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck 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): Amifostine is an organic thiophosphate cytoprotective agent indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer or non-small cell lung cancer and also to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer. Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite, believed to be responsible for the reduction of the cumulative renal toxicity of cisplatin and for the reduction of the toxic effects of radiation on normal oral tissues. Healthy cells are preferentially protected because amifostine and metabolites are present in healthy cells at 100-fold greater concentrations than in tumour 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): The thiol metabolite is responsible for most of the cytoprotective and radioprotective properties of amifostine. It is readily taken up by cells where it binds to and detoxifies reactive metabolites of platinum and alkylating agents as well as scavenges free radicals. Other possible effects include inhibition of apoptosis, alteration of gene expression and modification of enzyme activity. •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): Amifostine is rapidly dephosphorylated by alkaline phosphatase in tissues primarily to the active free thiol metabolite and, subsequently, to a less active disulfide metabolite. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After a 10-second bolus dose of 150 mg/m2 of ETHYOL, renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 8 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): Rat LD 50: 826 mg/kg •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Ethyol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amifostina (common) Amifostine (common) Amifostine anhydrous Amifostinum (common) Aminopropylaminoethyl thiophosphate (common) Ethiofos (common)

Do Abaloparatide and Amiloride interact?

•Drug A: Abaloparatide •Drug B: Amiloride •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amiloride 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 adjunctive treatment with thiazide diuretics or other kaliuretic-diuretic agents in congestive heart failure or 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): Amiloride, an antikaliuretic-diuretic agent, is a pyrazine-carbonyl-guanidine that is unrelated chemically to other known antikaliuretic or diuretic agents. It is an antihypertensive, potassium-sparing diuretic that was first approved for use in 1967 and helps to treat hypertension and congestive heart failure. The drug is often used in conjunction with thiazide or loop diuretics. Due to its potassium-sparing capacities, hyperkalemia (high blood potassium levels) are occasionally observed in patients taking amiloride. The risk is high in concurrent use of ACE inhibitors or spironolactone. Patients are also advised not to use potassium-containing salt replacements. •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): Amiloride works by inhibiting sodium reabsorption in the distal convoluted tubules and collecting ducts in the kidneys by binding to the amiloride-sensitive sodium channels. This promotes the loss of sodium and water from the body, but without depleting potassium. Amiloride exerts its potassium sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule and collecting duct; this decreases the net negative potential of the tubular lumen and reduces both potassium and hydrogen secretion and their subsequent excretion. Amiloride is not an aldosterone antagonist and its effects are seen even in the absence of aldosterone. •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): Readily absorbed following oral 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): Amiloride is not metabolized by the liver but is excreted unchanged by the kidneys. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Amiloride HCl is not metabolized by the liver but is excreted unchanged by the kidneys. About 50 percent of a 20 mg dose of amiloride HCl is excreted in the urine and 40 percent in the stool within 72 hours. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Plasma half-life varies from 6 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): 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 data are available in regard to overdosage in humans. The oral LD 50 of amiloride hydrochloride (calculated as the base) is 56 mg/kg in mice and 36 to 85 mg/kg in rats, depending on the strain. The most likely signs and symptoms to be expected with overdosage are dehydration and electrolyte imbalance. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Midamor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3,5-diamino-N-carbamimidoyl-6-chloropyrazine-2-carboxamide Amilorid (common) Amilorida (common) Amiloride (common) Amiloridum (common) Amipramidin (common) Amipramidine (common) Amyloride (common) N-amidino-3,5-diamino-6-chloropyrazinecarboxamide

Do Abaloparatide and Amiodarone interact?

•Drug A: Abaloparatide •Drug B: Amiodarone •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amiodarone 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 FDA approved indications for amiodarone are recurrent ventricular fibrillation (VF) and recurrent hemodynamically unstable ventricular tachycardia (VT). The FDA emphasizes that this drug should only be given in these conditions when they are clinically documented and have not responded to normal therapeutic doses of other antiarrhythmic agents, or when other drugs are not tolerated by the patient. Off-label indications include atrial fibrillation and supraventricular tachycardia. •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): After intravenous administration, amiodarone acts to relax smooth muscles that line vascular walls, decreases peripheral vascular resistance (afterload), and increases the cardiac index by a small amount. Administration by this route also decreases cardiac conduction, preventing and treating arrhythmias. When it is given orally, however, amiodarone does not lead to significant changes in the left ventricular ejection fraction. Similar to other anti-arrhythmic agents, controlled clinical trials do not confirm that oral amiodarone increases survival. Amiodarone prolongs the QRS duration and QT interval. In addition, a decreased SA (sinoatrial) node automaticity occurs with a decrease in AV node conduction velocity. Ectopic pacemaker automaticity is also inhibited. Thyrotoxicosis or hypothyroidism may also result from the administration of amiodarone, which contains high levels of iodine, and interferes with normal thyroid function. •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): Amiodarone is considered a class III anti-arrhythmic drug. It blocks potassium currents that cause repolarization of the heart muscle during the third phase of the cardiac action potential. As a result amiodarone increases the duration of the action potential as well as the effective refractory period for cardiac cells (myocytes). Therefore, cardiac muscle cell excitability is reduced, preventing and treating abnormal heart rhythms. Unique from other members of the class III anti-arrhythmic drug class, amiodarone also interferes with the functioning of beta-adrenergic receptors, sodium channels, and calcium channels channels. These actions, at times, can lead to undesirable effects, such as hypotension, bradycardia, and Torsades de pointes (TdP). In addition to the above, amiodarone may increase activity of peroxisome proliferator-activated receptors, leading to steatogenic changes in the liver or other organs. Finally, amiodarone has been found to bind to the thyroid receptor due to its iodine content, potentially leading to amiodarone induced hypothyroidism or thyrotoxicosis. •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 Cmax of amiodarone in the plasma is achieved about 3 to 7 hours after administration. The general time to onset of action of amiodarone after one dose given by the intravenous route is between 1 and 30 minutes, with therapeutic effects lasting from 1-3 hours. Steady-state concentrations of amiodarone in the plasma ranges between 0.4 to 11.99 μg/ml; it is advisable that steady-state levels are generally maintained between 1.0 and 2.5 μg/ml in patients with arrhythmias. Interestingly, its onset of action may sometimes begin after 2 to 3 days, but frequently takes 1 to 3 weeks, despite the administration of higher loading doses. The bioavailability of amiodarone varies in clinical studies, averaging between 35 and 65%. Effect of food In healthy subjects who were given a single 600-mg dose immediately after consuming a meal high in fat, the AUC of amiodarone increased by 2.3 and the Cmax by 3.8 times. Food also enhances absorption, reducing the Tmax by about 37%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): In a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients. Prescribing information mentions that the volume of distribution of amiodarone varies greatly, with a mean distribution of approximately 60 L/kg. It accumulates throughout the body, especially in adipose tissue and highly vascular organs including the lung, liver, and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), is found in even higher proportions in the same tissues as amiodarone. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The protein binding of amiodarone is about 96%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): This drug is metabolized to the main metabolite desethylamiodarone (DEA) by the CYP3A4 and CYP2C8 enzymes. The CYP3A4 enzyme is found in the liver and intestines. A hydroxyl metabolite of DEA has been identified in mammals, but its clinical significance is unknown. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion. A small amount of desethylamiodarone (DEA) is found in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal half-life of amiodarone varies according to the patient, but is long nonetheless, and ranges from about 9-100 days. The half-life duration varies according to different sources. According to the prescribing information for amiodarone, the average apparent plasma terminal elimination half-life of amiodarone is of 58 days (ranging from 15 to 142 days). The terminal half-life range was between 14 to 75 days for the active metabolite, (DEA). The plasma half-life of amiodarone after one dose ranges from 3.2 to 79.7 hours, according to one source. •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 amiodarone after intravenous administration in patients with ventricular fibrillation and ventricular tachycardia ranged from 220 to 440 ml/hr/kg in one clinically study. Another study determined that the total body clearance of amiodarone varies from 0.10 to 0.77 L/min after one intravenous dose. Renal impairment does not appear to affect the clearance of amiodarone, but hepatic impairment may reduce clearance. Patients with liver cirrhosis exhibited significantly lower Cmax and mean amiodarone concentration for DEA, but not for amiodarone. Severe left ventricular dysfunction prolongs the half-life of DEA. A note on monitoring No guidelines have been developed for adjusting the dose of amiodarone in renal, hepatic, or cardiac abnormalities. In patients on chronic amiodarone treatment, close clinical monitoring is advisable, especially for elderly patients and those with severe left ventricular dysfunction. •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 LD50 of oral amiodarone in mice and rats exceeds 3,000 mg/kg. An overdose with amiodarone can have a fatal outcome due to its potential to cause arrhythmia. Signs or symptoms of an overdose may include, hypotension, shock, bradycardia, AV block, and liver toxicity. In cases of an overdose, initiate supportive treatment and, if needed, use fluids, vasopressors, or positive inotropic agents. Temporary pacing may be required for heart block. Ensure to monitor liver function regularly. Amiodarone and its main metabolite, DEA, are not removable by dialysis. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Nexterone, Pacerone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-Butyl-3-(3,5-diiodo-4-(2-diethylaminoethoxy)benzoyl)benzofuran 2-Butyl-3-benzofuranyl 4-(2-(diethylamino)ethoxy)-3,5-diiodophenyl ketone 2-n-Butyl-3',5'-diiodo-4'-N-diethylaminoethoxy-3-benzoylbenzofuran Amiodarona (common) Amiodarone (common) Amiodaronum (common)

Do Abaloparatide and Amlodipine interact?

•Drug A: Abaloparatide •Drug B: Amlodipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amlodipine 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): Amlodipine may be used alone or in combination with other antihypertensive and antianginal agents for the treatment of the following conditions: • Hypertension • Coronary artery disease • Chronic stable angina • Vasospastic angina (Prinzmetal’s or Variant angina) • Angiographically documented coronary artery disease in patients without heart failure or an ejection fraction < 40% •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): General pharmacodynamic effects Amlodipine has a strong affinity for cell membranes, modulating calcium influx by inhibiting selected membrane calcium channels. This drug's unique binding properties allow for its long-acting action and less frequent dosing regimen,. Hemodynamic effects After the administration of therapeutic doses of amlodipine to patients diagnosed with hypertension, amlodipine causes vasodilation, which results in a reduction of supine and standing blood pressure. During these blood pressure reductions, there are no clinically significant changes in heart rate or plasma catecholamine levels with long-term use. Acute intravenous administration of amlodipine reduces arterial blood pressure and increases heart rate in patients with chronic stable angina, however, chronic oral administration of amlodipine in clinical studies did not cause clinically significant alterations in heart rate or blood pressures in patients diagnosed with angina and normal blood pressure. With long-term, once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Electrophysiologic effects Amlodipine does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in animals or humans. In patients who were diagnosed with chronic stable angina, the intravenous administration of 10 mg of amlodipine did not cause clinically significant alterations A-H and H-V conduction and sinus node recovery time after cardiac pacing. Patients administered amlodipine with concomitant beta-blockers produced similar results. In clinical trials in which amlodipine was given in combination with beta-blockers to patients diagnosed with hypertension or angina, no adverse effects on electrocardiographic parameters were noted. In clinical studies comprised of angina patients alone, amlodipine did not change electrocardiographic intervals or produce high degrees of AV block. Effects on angina Amlodipine relieves the symptoms of chest pain associated with angina. In patients diagnosed with angina, daily administration of a single amlodipine dose increases total exercise time, the time to angina onset, and the time to 1 mm ST-segment depression on ECG studies, decreases anginal attack frequency, and decreases the requirement for nitroglycerin tablets. •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): Mechanism of action on blood pressure Amlodipine is considered a peripheral arterial vasodilator that exerts its action directly on vascular smooth muscle to lead to a reduction in peripheral vascular resistance, causing a decrease in blood pressure. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the influx of calcium ions into both vascular smooth muscle and cardiac muscle. Experimental studies imply that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites, located on cell membranes. The contraction of cardiac muscle and vascular smooth muscle are dependent on the movement of extracellular calcium ions into these cells by specific ion channels. Amlodipine blocks calcium ion influx across cell membranes with selectivity. A stronger effect of amlodipine is exerted on vascular smooth muscle cells than on cardiac muscle cells. Direct actions of amlodipine on vascular smooth muscle result in reduced blood pressure. Mechanism of action in angina The exact mechanism by which amlodipine relieves the symptoms of angina have not been fully elucidated to this date, however, the mechanism of action is likely twofold: Amlodipine has a dilating effect on peripheral arterioles, reducing the total peripheral resistance (afterload) against which the cardiac muscle functions. Since the heart rate remains stable during amlodipine administration, the reduced work of the heart reduces both myocardial energy use and oxygen requirements. Dilatation of the main coronary arteries and coronary arterioles, both in healthy and ischemic areas, is another possible mechanism of amlodipine reduction of blood pressure. The dilatation causes an increase in myocardial oxygen delivery in patients experiencing coronary artery spasm (Prinzmetal's or variant angina) and reduces coronary vasoconstriction caused by smoking. •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): Amlodipine absorbed slowly and almost completely from the gastrointestinal tract. Peak plasma concentrations are achieved 6-12 hours after oral administration. The estimated bioavailability of amlodipine is 64-90%. Steady-state plasma amlodipine levels are achieved after 7-8 days of consecutive daily dosing. Absorption is not affected by food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 21 L/kg,. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): About 98%,. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Amlodipine is heavily (approximately 90%) converted to inactive metabolites via hepatic breakdown with 10% of the parent compound and 60% of the metabolites found excreted in the urine. Ex vivo studies have shown that about 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Characteristics that add to amlodipine's unique pharmacologic profile include nearly complete absorption, late-peak plasma concentrations, high bioavailability, and slow hepatic breakdown. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Elimination from the plasma occurs in a biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7-8 days of consecutive daily dosing. Amlodipine is 10% excreted as unchanged drug in the urine. Amlodipine can be initiated at normal doses in patients diagnosed with renal failure,. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half-life of about 30–50 hours. Plasma elimination half-life is 56 hours in patients with impaired hepatic function, titrate slowly when administering this drug to patients with severe hepatic impairment. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total body clearance (CL) has been calculated as 7 ± 1.3 ml/min/kg (0.42 ± 0.078 L/ h/kg) in healthy volunteers,. Elderly patients show a reduced clearance of amlodipine with an AUC (area under the curve) increase of about 40–60%, and a lower initial dose may be required. •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 toxicity (LD50): 37 mg/kg (mouse). Overdose An overdose of amlodipine could result in a high degree of peripheral vasodilatation with a possibility of reflex tachycardia. Significant and prolonged hypotension leading to shock and fatal outcomes have been reported. Carcinogenesis, mutagenesis, impairment of fertility Rats and mice treated with amlodipine maleate in the diet on a long-term basis for up to 2 years demonstrated no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was comparable to the maximum recommended human dose of 10 mg amlodipine per day. For the rat, the highest dose was measured to be about twice the maximum recommended human dose. Mutagenicity studies using amlodipine maleate showed no drug-related gene or chromosomal effects. There was no impact on the fertility of rats given oral amlodipine maleate (males for 64 days and females for 14 days before mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose). Use in pregnancy The safety of amlodipine in human pregnancy or lactation has not been proven. Amlodipine is therefore considered a pregnancy category C drug. Use amlodipine only if the potential benefit justifies the potential risk. Use in nursing Discontinue when administering amlodipine. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Amlobenz, Azor, Caduet, Dafiro, Exforge, Exforge Hct, Katerzia, Lotrel, Norliqva, Norvasc, Prestalia, Tribenzor, Twynsta, Viacoram •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (RS)-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate 3-Ethyl 5-methylester, (±)-2-[(2-aminoethoxy)methyl]-4-(o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate Amlodipine (common) Amlodipine free base Amlodipino (common) Amlodipinum (common)

Do Abaloparatide and Amobarbital interact?

•Drug A: Abaloparatide •Drug B: Amobarbital •Severity: MODERATE •Description: Amobarbital 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): 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): Amobarbital (like all barbiturates) works by binding to the GABAA receptor at either the alpha or the beta sub unit. These are binding sites that are distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. This GABAA receptor binding decreases input resistance, depresses burst and tonic firing, especially in ventrobasal and intralaminar neurons, while at the same time increasing burst duration and mean conductance at individual chloride channels; this increases both the amplitude and decay time of inhibitory postsynaptic currents. In addition to this GABA-ergic effect, barbiturates also block the AMPA receptor, a subtype of glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Amobarbital also appears to bind neuronal nicotinic acetylcholine 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): 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): 5-ethyl-5-(3-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione 5-ethyl-5-(3-methylbutyl)barbituric acid 5-ethyl-5-isoamylbarbituric acid 5-ethyl-5-isopentylbarbituric acid Amobarbital (common) Amobarbitale (common) Amylobarbitone (common) Barbamil (common) Barbamyl (common)

Do Abaloparatide and Amphotericin B interact?

•Drug A: Abaloparatide •Drug B: Amphotericin B •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amphotericin B 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 to treat potentially life threatening fungal infections. •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): Amphotericin B shows a high order of in vitro activity against many species of fungi. Histoplasma capsulatum, Coccidioides immitis, Candida species, Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenckii, Mucor mucedo, and Aspergillus fumigatus are all inhibited by concentrations of amphotericin B ranging from 0.03 to 1.0 mcg/mL in vitro. While Candida albicans is generally quite susceptible to amphotericin B, non- albicans species may be less susceptible. Pseudallescheria boydii and Fusarium sp. are often resistant to amphotericin B. The antibiotic is without effect on bacteria, rickettsiae, and viruses. •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): Amphotericin B is fungistatic or fungicidal depending on the concentration obtained in body fluids and the susceptibility of the fungus. The drug acts by binding to sterols (ergosterol) in the cell membrane of susceptible fungi. This creates a transmembrane channel, and the resultant change in membrane permeability allowing leakage of intracellular components. Ergosterol, the principal sterol in the fungal cytoplasmic membrane, is the target site of action of amphotericin B and the azoles. Amphotericin B, a polyene, binds irreversibly to ergosterol, resulting in disruption of membrane integrity and ultimately cell death. •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 is 100% for intravenous infusion. •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): Highly bound (>90%) to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Exclusively renal •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): An elimination half-life of approximately 15 days follows an initial plasma half-life of about 24 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 39 +/- 22 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 1 mg/kg/day at Day 1] 17 +/- 6 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 1 mg/kg/day 3-20 days later] 51 +/- 44 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 2.5 mg/kg/day at Day 1] 22 +/- 15 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 2.5 mg/kg/day 3-20 days later] 21 +/- 14 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 5 mg/kg/day at Day 1] 11 +/- 6 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 5 mg/kg/day 3-20 days later] •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, rat: LD 50 = >5 gm/kg. Amphotericin B overdoses can result in cardio-respiratory arrest. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Abelcet, Ambisome, Amphotec, Fungizone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Amyl Nitrite interact?

•Drug A: Abaloparatide •Drug B: Amyl Nitrite •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amyl Nitrite 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 rapid relief of angina pectoris. •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): Amyl nitrite, in common with other alkyl nitrites, is a potent vasodilator. It expands blood vessels, resulting in lowering of the blood pressure. Alkyl nitrite functions as a source of nitric oxide, which signals for relaxation of the involuntary muscles. Adverse effects are related to this pharmacological activity and include hypotension, headache, flushing of the face, tachycardia, dizziness, and relaxation of involuntary muscles, especially the blood vessel walls and the anal sphincter. •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): Amyl nitrite's antianginal action is thought to be the result of a reduction in systemic and pulmonary arterial pressure (afterload) and decreased cardiac output because of peripheral vasodilation, rather than coronary artery dilation. Amyl nitrite is a source of nitric oxide, which accounts for the mechanism described above. As an antidote (to cyanide poisoning), amyl nitrite promotes formation of methemoglobin, which combines with cyanide to form nontoxic cyanmethemoglobin. •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): Amyl nitrite vapors are absorbed rapidly through the pulmonary alveoli, manifesting therapeutic effects within one minute 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): Hepatic. The drug is metabolized rapidly, probably by hydrolytic denitration; approximately one-third of the inhaled amyl nitrite 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): 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): Overdose symptoms include nausea, emesis (vomiting), hypotension, hypoventilation, dyspnea (shortness of breath), and syncope (fainting) •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 Apomorphine interact?

•Drug A: Abaloparatide •Drug B: Apomorphine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Apomorphine 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): Apomorphine is indicated to treat acute, intermittent treatment of hypomobility, off episodes associated with advanced 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): Apomorphine is a dopaminergic agonist that may stimulate regions of the brain involved in motor control. It has a short duration of action and a wide therapeutic index as large overdoses are necessary for significant toxicity. Patients should be counselled regarding the risk of nausea, vomiting, daytime somnolence, hypotension, oral mucosal irritation, falls, hallucinations, psychotic-like behaviour, impulsive behaviour, withdrawal hyperpyrexia, and prolongation of the QT interval. Given the incidence of nausea and vomiting in patients taking apomorphine, treatment with trimethobenzamide may be recommended prior to or during therapy. Antiemetic pretreatment may be started three days prior to beginning therapy with apomorphine - it should only be continued as long as is necessary and generally for no longer than two months. •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): Apomorphine is a non-ergoline dopamine agonist with high binding affinity to dopamine D2, D3, and D5 receptors. Stimulation of D2 receptors in the caudate-putamen, a region of the brain responsible for locomotor control, may be responsible for apomorphine's action. However, the means by which the cellular effects of apomorphine treat hypomobility of Parkinson's remain 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): Apomorphine has a plasma T max of 10-20 minutes and a cerebrospinal fluid T max. The C max and AUC of apomorphine vary significantly between patients, with 5- to 10-fold differences being reported. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution of subcutaneous apomorphine is 123-404L with an average of 218L. The apparent volume of distribution of sublingual apomorphine is 3630L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Apomorphine is expected to be 99.9% bound to human serum albumin, as no unbound apomorphine is detected. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Apomorphine is N-demethylated by CYP2B6, 2C8, 3A4, and 3A5. It can be glucuronidated by various UGTs, or sulfated by SULTs 1A1, 1A2, 1A3, 1E1, and 1B1. Approximately 60% of sublingual apomorphine is eliminated as a sulfate conjugate, though the structure of these sulfate conjugates are not readily available. The remainder of an apomorphine dose is eliminated as apomorphine glucuronide and norapomorphine glucuronide. Only 0.3% of subcutaneous apomorphine is recovered as the unchanged parent drug. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Data regarding apomorphine's route of elimination is not readily available. A study in rats has shown apomorphine is predominantly eliminated in the 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 a 15mg sublingual dose of apomorphine is 1.7h, while the terminal elimination half life of an intravenous dose is 50 minutes. •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 a 15mg sublingual dose of apomorphine is 1440L/h, while the clearance of an intravenous dose is 223L/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 of apomorphine may present with nausea, hypotension, and loss of consciousness. Treat patients with symptomatic and supportive measures. The intraperitoneal LD 50 in mice is 145µg/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Apokyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (−)-10,11-dihydroxyaporphine (6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol (R)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol Apomorfina (common) Apomorphin (common) Apomorphine (common) R-(−)-apomorphine

Do Abaloparatide and Aripiprazole lauroxil interact?

•Drug A: Abaloparatide •Drug B: Aripiprazole lauroxil •Severity: MINOR •Description: Aripiprazole lauroxil may increase the hypotensive activities of Abaloparatide. •Extended Description: Aripiprazole may cause orthostatic hypotension through antagonism of the α1-adrenergic receptor.3,2,4 Cases of orthostatic hypotension, postural dizziness, and syncope have been reported with the short-term use of aripiprazole in clinical trials. The risk for developing a decrease in blood pressure may be enhanced with concurrent use of aripiprazole with other agents known to cause hypotension, including antihypertensive medications. Contrary to these findings, one case report looking at two patients found that aripiprazole may increase hypertension. •References: 1. Yasui-Furukori N, Fujii A: Worsened hypertension control induced by aripiprazole. Neuropsychiatr Dis Treat. 2013;9:505-7. doi: 10.2147/NDT.S43950. Epub 2013 Apr 15. [https://go.drugbank.com/articles/A37406] 2. Wang YC: Dose-related reversible hypotension during aripiprazole treatment. J Neuropsychiatry Clin Neurosci. 2013 Winter;25(1):E33. doi: 10.1176/appi.neuropsych.12030046. [https://go.drugbank.com/articles/A37407] 3. Torgovnick J, Sethi NK, Arsura E: Aripiprazole-induced orthostatic hypotension and cardiac arrhythmia. Psychiatry Clin Neurosci. 2008 Aug;62(4):485. doi: 10.1111/j.1440-1819.2008.01833.x. [https://go.drugbank.com/articles/A37408] •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): Aripiprazole lauroxil is indicated for the treatment of schizophrenia and related psychotic 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): Aripiprazole, which is a major pharmacological metabolite of aripiprazole lauroxil, serves to improve the positive and negative symptoms of schizophrenia by modulating dopaminergic signalling pathways. Aripiprazole lauroxil is reported to have minimal effects on sexual function or prolactin levels. •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 pharmacological activity of aripiprazole lauroxil is thought to be mainly mediated by its metabolite aripiprazole, and to a lesser extent, dehydro-aripiprazole. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at the serotonin 5-HT2A receptor. The desired outcome of antipsuchotic agents in schizophrenia is to inhibit dopaminergic transmission in the limbic system and enhance dopaminergic transmission in the prefrontal cortex. As a partial agonist at D2 receptors in the mesolimbic dopaminergic pathway, aripiprazole acts as a functional antagonist in the mesolimbic dopamine pathway and reduces the extent of dopaminergic pathway activity. This results in reduced positive symptoms in schizophrenia and extrapyramidal motor side effects. In contrast, aripiprazole is thought to act as a functional agonist in the mesocortical pathway, where reduced dopamine activity is seen in association with negative symptoms and cognitive impairment. Antagonism at 5-HT2A receptors by aripiprazole alleviates the negative symptoms and cognitive impairment of schizophrenia. 5-HT2A receptors are Gi/Go-coupled that upon activation, produce neuronal inhibition via decreased neuronal excitability and decreased transmitter release at the nerve terminals. In the nigrostriatal pathway, 5-HT2A regulates the release of dopamine. Through antagonism of 5-HT2A receptors, aripiprazole disinhibits the release of dopamine in the striatum and enhance the levels of the transmitters at the nerve terminals. The combined effects of D2 and 5-HT2A antagonism are thought to counteract the increased dopamine function causing increased extrapyramidal side effects. Blocking 5-HT2A receptors may also lead to the modulation of glutamate release in the mesocortical circuit, which is a transmitter that plays a role in schizophrenia. 5-HT1A receptors are autoreceptors that inhibit 5-HT release upon activation. Aripiprazole is a partial agonist at theses receptors and reduces 5-HT release; this results in potentiated dopamine release in the striatum and prefrontal cortex. It is reported that therapeutic doses of aripiprazole occupies up to 90% of brain D2 receptors in a dose-dependent manner. Apripiprazole targets different receptors that lead to drug-related adverse reactions; for example, the antagonist activity at the alpha-1 adrenergic receptors results in orthostatic hypotension. Aripiprazole's antagonism of histamine H1 receptors may explain the somnolence observed with this 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 a single extended-release intramuscular injection of aripiprazole lauroxil, aripiprazole can be detected in the systemic circulation from 5 to 6 days and is continued to be released for an additional 36 days. The concentrations of aripiprazole increases with consecutive doses of aripiprazole lauroxil and the steady state is reached following the fourth monthly injection. The systemic exposure to aripiprazole was similar when comparing deltoid and gluteal intramuscular injections. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Based on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of aripiprazole lauroxil was 268 L, indicating extensive extravascular distribution following absorption. Health human volunteer study indicates that aripiprazole crosses the blood-brain barrier. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Serum protein binding of aripiprazole and its major metabolite is >99% at therapeutic concentrations, where they are primarily bound to albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Aripiprazole lauroxil is hydrolyzed to form N-hydroxymethyl-aripiprazole via esterases. N-hydroxymethyl-aripiprazole undergoes a rapid, nonenzymatic spontaneous cleavage, or water-mediated hydrolysis, to form aripiprazole, which mainly contributes to the pharmacological actions of aripiprazole lauroxil. Aripiprazole is further metabolized by hepatic CYP3A4 and CYP2D6 to form dehydro-aripiprazole, which retains some pharmacological activity. Dehydro-aripiprazole displays affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma. Cytochrome P450 2D6 is subject to genetic polymorphism, which results in pharmacokinetic differences among CYP2D6 metabolizer phenotypes and dosage adjustments accordingly. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Based on the pharmacokinetic study for aripiprazole, less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean aripiprazole terminal elimination half-life ranged from 29.2 days to 34.9 days after every 4-week injection of aripiprazole lauroxil 441, 662 and 882 mg. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): In rats, the clearance for aripiprazole lauroxil was 0.32 ± 0.11 L/h/kg following injection of aripiprazole lauroxil molar equivalent to 5 mg aripiprazole/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): LD50 in rat following intramuscular injection was >60 mg aripiprazole equivalents. Oral LD50 of aripiprazole in female rat, male rat, and monkey were 705 mg/kg, 965 mg/kg, and >2000 mg/kg, respectively. Most common adverse reaction of aripiprazole was akathisia. A case of drug overdosage occurred followinga acute ingestion of 1260 mg aripiprazole, which is approximately 42 times the maximum recommended daily dose. Overdose was associated with vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. Aripiprazole is an antipsychotic drug that may develop Neuroleptic Malignant Syndrome (NMS), which is manifested with hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. In case of NMS, aripiprazole should be discontinued immediately, and intensive symptomatic treatment and medical monitoring should be initiated. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Aristada •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Aripiprazole interact?

•Drug A: Abaloparatide •Drug B: Aripiprazole •Severity: MINOR •Description: Aripiprazole may increase the hypotensive activities of Abaloparatide. •Extended Description: Aripiprazole may cause orthostatic hypotension through antagonism of the α1-adrenergic receptor.3,2,4 Cases of orthostatic hypotension, postural dizziness, and syncope have been reported with the short-term use of aripiprazole in clinical trials. The risk for developing a decrease in blood pressure may be enhanced with concurrent use of aripiprazole with other agents known to cause hypotension, including antihypertensive medications. Contrary to these findings, one case report looking at two patients found that aripiprazole may increase hypertension. •References: 1. Yasui-Furukori N, Fujii A: Worsened hypertension control induced by aripiprazole. Neuropsychiatr Dis Treat. 2013;9:505-7. doi: 10.2147/NDT.S43950. Epub 2013 Apr 15. [https://go.drugbank.com/articles/A37406] 2. Wang YC: Dose-related reversible hypotension during aripiprazole treatment. J Neuropsychiatry Clin Neurosci. 2013 Winter;25(1):E33. doi: 10.1176/appi.neuropsych.12030046. [https://go.drugbank.com/articles/A37407] 3. Torgovnick J, Sethi NK, Arsura E: Aripiprazole-induced orthostatic hypotension and cardiac arrhythmia. Psychiatry Clin Neurosci. 2008 Aug;62(4):485. doi: 10.1111/j.1440-1819.2008.01833.x. [https://go.drugbank.com/articles/A37408] •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): Aripiprazole is indicated for the treatment of acute manic and mixed episodes associated with bipolar I disorder, irritability associated with autism spectrum disorder, schizophrenia, and Tourette's disorder. It is also used as an adjunctive treatment of major depressive disorder.[L45859 An injectable formulation of aripiprazole is indicated for agitation associated with schizophrenia or bipolar mania. Finally, an extended-release, bimonthly injection formulation of aripiprazole is indicated for the treatment of adult schizophrenia and maintenance therapy for adult bipolar I 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): Aripiprazole exhibits high affinity for dopamine D 2 and D 3, serotonin 5-HT 1a and 5-HT 2a receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D 4, serotonin 5-HT 2c and 5-HT 7, alpha 1 -adrenergic and histamine H 1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM). •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 antipsychotic action of aripiprazole is likely due to its partial agonist activity on D2 and 5-HT 1A receptors as well as its antagonist activity at 5-HT 2A receptors; however, the exact mechanism has not been fully elucidated. One of the mechanisms that have been proposed is that aripiprazole both stimulates and inhibits dopamine as it engages the D2 receptor. It lowers dopamine neuronal firing at high dopamine concentrations and increases dopamine firing at low concentrations. Its partial agonist activity gives aripiprazole an intermediate level of dopaminergic neuronal tone between full agonist and antagonist of the D2 receptor. In addition, some adverse effects may be due to action on other receptors.[L4620] For example, orthostatic hypotension may be explained by antagonism of the adrenergic alpha-1 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): Tablet: Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%. ABILIFY can be administered with or without food. Administration of a 15 mg ABILIFY tablet with a standard high-fat meal did not significantly affect the C max or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T max by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole. Oral Solution: Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher than that from the tablet formulation. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution-to-tablet ratios of geometric mean C max and AUC values were 122% and 114%, respectively. The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional between the doses of 5 mg to 30 mg. Extended-release injectable suspension, bimonthly injection: Aripiprazole absorption into the systemic circulation is prolonged following gluteal intramuscular injection due to the low solubility of aripiprazole particles. The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over 2 months following gluteal injection(s). Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with T max ranging between 1 to 49 days following multiple gluteal administrations of 960 mg. •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 aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively. For populations that are poor CYP2D6 metabolizers, the half-life of aripiprazole is 146 hours and these patients should be treated with half the normal dose. Other studies have reported a half-life of 61.03±19.59 hours for aripiprazole and 279±299 hours for the active metabolite. •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 aripiprazole was estimated to be 0.8mL/min/kg. Other studies have also reported a clearance rate of 3297±1042mL/hr. •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): Neonates exposed to antipsychotic drugs, including ABILIFY, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotics, including ABILIFY, during pregnancy. In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival. ABILIFY has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral ABILIFY have been reported worldwide. These include overdoses with oral ABILIFY alone and in combination with other substances. No fatality was reported with ABILIFY alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral ABILIFY (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving oral ABILIFY ingestions up to 195 mg with no fatalities. Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral ABILIFY overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with ABILIFY overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. No specific information is available on the treatment of overdose with ABILIFY. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Charcoal: In the event of an overdose of ABILIFY, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of ABILIFY, decreased the mean AUC and C max of aripiprazole by 50%. Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with ABILIFY, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins. Lifetime carcinogenicity studies were conducted in ICR mice, F344 rats, and Sprague-Dawley (SD) rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2, 0.5, 2 and 5 times and 0.3, 1 and 3 times the MRHD of 30 mg/day based on mg/m2 body surface area, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day, which are 3, 6, 13 and 19 times the MRHD based on mg/m2 body surface area. Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the MRHD). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the MRHD); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (19 times the MRHD). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2-receptor antagonism and hyperprolactinemia. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13 week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4 week and 13 week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear. The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, increased numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans. Female rats were treated orally with aripiprazole from 2 weeks prior to mating through gestation Day 7 at doses of 2, 6, and 20 mg/kg/day, which are 0.6, 2, and 6 times the MRHD of 30 mg/day based on mg/m2 body surface area. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 2 and 6 times the MRHD, and decreased fetal weight was seen at 6 times the MRHD. Male rats were treated orally with aripiprazole from 9 weeks prior to mating through mating at doses of 20, 40, and 60 mg/kg/day, which are 6, 13, and 19 times the MRHD of 30 mg/day based on mg/m2 body surface area. Disturbances in spermatogenesis were seen at 19 times the MRHD and prostate atrophy was seen at 13 and 19 times the MRHD without impairment of fertility. Pharmacokinetic properties in patients 10-17 years of age are similar to that of adults once body weight has been corrected for. No dosage adjustment is necessary in elderly patients however aripiprazole is not approved for Alzheimer's associated psychosis. Patients classified as CYP2D6 poor metabolizers should be prescribed half the regular dose of aripiprazole. Hepatic and renal function as well as sex, race, and smoking status do not affect dosage requirements for aripiprazole •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Abilify •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Arsenic trioxide interact?

•Drug A: Abaloparatide •Drug B: Arsenic trioxide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Arsenic trioxide 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 induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression •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): Arsenic Trioxide is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy. •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 Arsenic Trioxide is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha. It is suspected that arsenic trioxide induces cancer cells to undergo apoptosis. •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): 75% bound •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Inorganic, lyophilized arsenic trioxide, when placed in solution, is immediately hydrolyzed to arsenous acid - this appears to be the pharmacologically active species of arsenic trioxide. Further metabolism involves the oxidation of arsenous acid to arsenic acid, and an oxidative methylation of arsenous acid to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) by methyltransferases in the liver. Both MMA and DMA have relatively long half-lives and can accumulate following multiple doses, the extent of which depends upon the dosing regimen in question. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Trivalent arsenic is mostly methylated in humans and excreted in urine. •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 overdose include convulsions, muscle weakness and confusion. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Trisenox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed

Do Abaloparatide and Atenolol interact?

•Drug A: Abaloparatide •Drug B: Atenolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Atenolol 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): Indicated for: 1) Management of hypertension alone and in combination with other antihypertensives. 2) Management of angina pectoris associated with coronary atherosclerosis. 3) Management of acute myocardial infarction in hemodynamically stable patients with a heart rate greater than 50 beats per minutes and a systolic blood pressure above 100 mmHg. Off-label uses include: 1) Secondary prevention of myocardial infarction. 2) Management of heart failure. 3) Management of atrial fibrillation. 4) Management of supraventricular tachycardia. 5) Management of ventricular arrythmias such as congenital long-QT and arrhythmogenic right ventricular cardiomyopathy. 6) Management of symptomatic thyrotoxicosis in combination with methimazole. 7) Prophylaxis of migraine headaches. 8) Management of alcohol withdrawal. •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): Atenolol is a cardio-selective beta-blocker and as such exerts most of its effects on the heart. It acts as an antagonist to sympathetic innervation and prevents increases in heart rate, electrical conductivity, and contractility in the heart due to increased release of norepinephrine from the peripheral nervous system. Together the decreases in contractility and rate produce a reduction in cardiac output resulting in a compensatory increase in peripheral vascular resistance in the short-term. This response later declines to baseline with long-term use of atenolol. More importantly, this reduction in the work demanded of the myocardium also reduces oxygen demand which provides therapeutic benefit by reducing the mismatch of oxygen supply and demand in settings where coronary blood flow is limited, such as in coronary atherosclerosis. Reducing oxygen demand, particularly due to exercise, can reduce the frequency of angina pectoris symptoms and potentially improve survival of the remaining myocardium after myocardial infarction. The decrease in rate of sinoatrial node potentials, electrical conduction, slowing of potentials traveling through the atrioventricular node, and reduced frequency of ectopic potentials due to blockade of adrenergic beta receptors has led to benefit in arrhythmic conditions such as atrial fibrillation by controlling the rate of action potential generation and allowing for more effective coordinated contractions. Since a degree of sympathetic activity is necessary to maintain cardiac function, the reduced contractility induced by atenolol may precipitate or worsen heart failure, especially during volume overload. The effects of atenolol on blood pressure have been established, although it is less effective than alternative beta-blockers, but the mechanism has not yet been characterized. As a β1 selective drug, it does not act via the vasodilation produced by non-selective agents. Despite this there is a sustained reduction in peripheral vascular resistance, and consequently blood pressure, alongside a decrease in cardiac output. It is thought that atenolol's antihypertensive activity may be related to action on the central nervous system (CNS) or it's inhibition of the renin-aldosterone-angiotensin system rather than direct effects on the vasculature. Atenolol produces CNS effects similar to other beta-blockers, but does so to a lesser extent due to reduces ability to cross the blood-brain barrier. It has the potential to produce fatigue, depression, and sleep disturbances such as nightmares or insomnia. The exact mechanisms behind these have not been characterized but their occurrence must be considered as they represent clinically relevant adverse effects. Atenolol exerts some effects on the respiratory system although to a much lesser extent than non-selective beta-blockers. Interaction with β2 receptors in the airways can produce bronchoconstriction by blocking the relaxation of bronchial smooth muscle mediated by the sympathetic nervous system. The same action can interfere with β-agonist therapies used in asthma and chronic obstructive pulmonary disease. Unlike some other beta-blocker drugs, atenolol does not have intrinsic sympathomimetic or membrane stabilizing activity nor does it produce changes in glycemic control. •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): Atenolol is a cardioselective beta-blocker, called such because it selectively binds to the β1-adrenergic receptor as an antagonist up to a reported 26 fold more than β2 receptors. Selective activity at the β1 receptor produces cardioselectivity due to the higher population of this receptor in cardiac tissue. Some binding to β2 and possibly β3 receptors can still occur at therapeutic dosages but the effects mediated by antagonizing these are significantly reduced from those of non-selective agents. β1 and β2 receptors are G s coupled therefore antagonism of their activation reduces activity of adenylyl cyclase and its downstream signalling via cyclic adenosime monophosphate and protein kinase A (PKA). In cardiomyocytes PKA is thought to mediate activation of L-type calcium channels and ryanodine receptors through their phosphorylation. L-type calcium channels can then provide an initial rise in intracellular calcium and trigger the ryanodine receptors to release calcium stored in the sarcoplasmic reticulum (SR) and increased contractility. PKA also plays a role in the cessation of contraction by phosphorylating phospholamban which in turn increases the affinity of SR Ca ATPase to increase reuptake of calcium into the SR. It also phophorylates troponin I to reduce affinity of the protein for calcium. Both of these events lead to a reduction in contraction which, when coupled with the initial increase in contraction, allows for faster cycling and consequently higher heart rate with increased contractility. L-type calcium channels are also a major contributor to cardiac depolarization and their activation can increase frequency of action potentials and possibly the incidence of ectopic potentials. Similar inihibitory events occur in the bronchial smooth muscle to mediate relaxation including phosphorylation of myosin light-chain kinase, reducing its affinity for calcium. PKA also inhibits the excitatory G q coupled pathway by phosphorylating the inositol trisphosphate receptor and phospholipase C resulting in inhibition of intracellular calcium release. Antagonism of this activity by beta-blocker agents like atenolol can thus cause increased bronchoconstriction. •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 50% of an oral dose is absorbed from the gastrointestinal tract, with the remainder being excreted unchanged in the feces. Administering atenolol with food can decrease the AUC by about 20%. While atenolol can cross the blood-brain barrier, it does so slowly and to a small extent. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Total Vd of 63.8-112.5 L. Atenolol distributes into a central volume of 12.8-17.5 L along with two peripheral compartments with a combined volume of 51-95 L. Distribution takes about 3 hrs for the central compartment, 4 hrs for the shallower peripheral compartment, and 5-6 hrs for the deeper peripheral compartment. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 6-16% bound in plasma. Atenolol binds to two sites on human serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Minimal metabolism in the liver. The sole non-conjugated metabolite is the product of a hydroxylation reaction at the carbon between the amide and benzene groups. The only other metabolite to be confirmed is a glucuronide conjugate. These metabolites make up 5-8% and 2% of the renally excreted dose with 87-90% appearing as unchanged drug. The hydroxylated metabolite is exerts 1/10th the beta-blocking activity of atenolol. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 85% is eliminated by the kidneys following IV administration with 10% appearing in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 6-7 hrs. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total clearance is estimated at 97.3-176.3 mL/min with a renal clearance of 95-168 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): LD 50 Values Mouse: 2 g/kg (Oral), 57 mg/kg (IV), 134 mg/kg (IP), 400 mg/kg (SC) Rat: 2 g/kg (Oral), 77 mg/kg (IV), 600 mg/kg (SC) Rabbit: 50 mg/kg (IV) Carcinogenicity & Mutagenicity Studies in rats and mice at doses of 300 mg/kg/day, equivalent to 150 times maximum recommended human dose, for durations of 18 and 24 months showed no carcinogenicity. One study in rats at doses of 500-1500 mg/kg/day, 250-750 times maximum human dose, resulted in increases benign adrenal medullary tumors in both sexes and increase mammary fibroadenomas in females. Atenolol showed no mutagenicity in the Ames test using S. typhinarium, dominant lethal test in mice, or in vivo cytogenetics test in chinese hamster ovary cells. Reproductive Toxicity No adverse effects on fertility were observed in either male or female mice after receiving doses of 200 mg/kg/day, equivalent to 200 times the maximum human dose. In humans, atenolol is known to cross the placenta and fetuses exposed to the drug have been reported to be smaller than expected considering gestational age. Embryo-fetal resorption has been observed in rats at doses of 50mg/kg/day, 50 times the max human dose, but not in rabbits at doses of 25mg/kg/day. Lactation Atenolol appears in breast milk at a ratio of 1.5-6.8 to plasma concentrations. It has been estimated that infant exposure occurs at 5.7-19.2% maternal weight-adjusted dosage. Effects in infants include bradycardia, hypothermia, and lethargy. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Tenoretic, Tenormin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-p-Carbamoylmethylphenoxy-3-isopropylamino-2-propanol 2-(p-(2-Hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide 4-(2-Hydroxy-3-((1-methylethyl)amino)propoxy)benzeneacetamide Atenolol (common) Atenololum (common)

Do Abaloparatide and Avanafil interact?

•Drug A: Abaloparatide •Drug B: Avanafil •Severity: MINOR •Description: The risk or severity of hypotension can be increased when Avanafil 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): Avanafil 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): Avanafil is a strong competitive inhibitor of phosphodiesterase 5 (PDE5) with a demonstrated in vitro IC 50 of 5.2 nM. Its inhibitory effects on PDE5 are 100-fold more potent than on PDE6 and >1000-fold more potent than on other PDE enzymes, meaning it is less likely to cause visual disturbances and cardiovascular adverse effects when compared with less selective PDE5 inhibitors such as sildenafil and vardenafil. It has a relatively quick onset of action allowing for administration as early as 15 minutes prior to sexual activity. PDE5 inhibitors like avanafil can cause significant drug interactions when administered alongside certain antihypertensive agents (e.g. alpha blockers, substantial amounts of alcohol). PDE5 inhibitors have also been associated with the development of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition that typically presents as sudden loss of vision in one or both eyes and appears to be more common in patients with a "crowded" optic disc. Patients presenting with any degree of vision loss should immediately discontinue use of all PDE5 inhibitors and seek medical attention. In some jurisdictions, a history of NAION or other degenerative retinal disorders is considered a contraindication to avanafil therapy. •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): Avanafil inhibits the cGMP-specific phosphodiesterase type 5 (PDE5) which is responsible for the degradation of cGMP in the corpus cavernosum located around the penis. Sexual arousal results in the local release of nitric oxide, which in turn stimulates the enzyme guanylate cyclase to produce cGMP. Elevated levels of cGMP result in local smooth muscle relaxation and increased blood flow to the penis (i.e. an erection). As PDE5 inhibitors like avanafil require the endogenous release of nitric oxide in order to exert their pharmacologic effect, they have no effect on the user in the absence of sexual stimulation/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): Avanafil is rapidly absorbed following oral administration (T max of 30-45 minutes) and appears to have low to moderate oral bioavailability, though formal studies have not been conducted. Administration with a meal results in a mean delay in T max of 1.12 to 1.25 hours, a 39% mean reduction in C max, and a negligible effect on AUC. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution of avanafil is 47 to 83 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Avanafil and its two major metabolites, M4 and M16, are highly protein-bound in plasma at approximately 99%, 97%, and 81%, respectively. Binding occurs primarily to albumin (99%), with smaller contributions from γ-globulin (43%) and α1-acid glycoprotein (66%). •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Avanafil is extensively metabolized, primarily by CYP3A4 and to a lesser extent by CYP2C9. There are two major metabolites formed, M4 and M16, which exist in the plasma at concentrations 23% and 29% that of the parent compound, respectively. The M16 metabolite lacks pharmacologic effect, but the M4 metabolite has an inhibitory potency for PDE5 18% that of avanafil and accounts for approximately 4% of the observed pharmacologic activity of avanafil. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following oral administration, avanafil is extensively metabolized. Approximately 62% of a given dose is excreted as metabolites in the feces and approximately 21% as metabolites in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Studies have demonstrated variability in the terminal elimination half-life of avanafil, with estimates ranging between 5 - 17 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): Experience with avanafil overdose is limited. Single doses of up to 800mg and repeat doses of up to 300mg have been administered - these patients experienced adverse effects similar to those seen at therapeutic doses but with increased incidence and severity. Patients experiencing an overdosage of avanafil should be treated with standard symptomatic and supportive measures. Dialysis is unlikely to be of benefit in cases of overdose as avanafil is highly protein-bound in plasma. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Spedra, Stendra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-4-(3-Chloro-4-methoxybenzylamino)-2-(2-hydroxymethylpyrrolidin-1-yl)-N-pyrimidin-2-ylmethyl-5-pyrimidinecarboxamide Avanafil (common) Avanafilo (common)

Do Abaloparatide and Azilsartan medoxomil interact?

•Drug A: Abaloparatide •Drug B: Azilsartan medoxomil •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Azilsartan medoxomil. •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): Azilsartan medoxomil is indicated for the treatment of hypertension to lower blood pressure in patients over 18 years of age. It may be used either alone or in combination with other antihypertensive agents. Some antihypertensive drugs have lesser effects on blood pressure in black patients. Azilsartan medoxomil is available as a fixed-dose combination product with chlorthalidone, which is indicated for the treatment of hypertension in patients whose hose blood pressure is not adequately controlled on monotherapy. It may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals. Azilsartan medoxomil belongs to the angiotensin-receptor blocking (ARB) class of drugs, which are used to decrease the progression of moderate-to-severe albuminuria and prevent the recurrence of atrial fibrillation as off-label uses in patients with diabetes mellitus 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): Pharmacodynamic effects of azilsartan medoxomil are mediated by its active metabolite, azilsartan. Azilsartan inhibits the pressor effects of an angiotensin II infusion in a dose-related manner. At a single 32 mg dose, azilsartan inhibited the maximal pressor effect by approximately 90% at peak plasma concentrations and by 60% at 24 hours after administration. In healthy subjects receiving single and repeated doses of azilsartan medoxomil, plasma angiotensin I and II concentrations and plasma renin activity increased, while plasma aldosterone concentrations decreased. Like other ARBs, azilsartan causes dose-dependent decrease in peripheral resistance and decreases smooth muscle vascular tone. As azilsartan blocks the angiotensin II receptor, the negative regulatory feedback of angiotensin II on renin secretion is inhibited; however, the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the blood pressure-lowering effect of azilsartan. Blood pressure-lowering effects of antihypertensive agents can be reduced in patients of African descent. However, there are no recommended dosage adjustment of azilsartan on the basis of a patient’s sex, race, or degree of renal or hepatic impairment. Azilsartan medoxomil has negligible effects on serum potassium or sodium levels. Azilsartan does not affect the biosynthesis of angiotensin II nor bradykinin levels. It also does not bind to any ion channels that are involved in cardiovascular regulation. •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 renin-angiotensin-aldosterone system regulates blood pressure. Angiotensin II is a peptide hormone that is a principal pressor agent in the renin-angiotensin-aldosterone system. It is a potent, direct vasoconstrictor that binds to the angiotensin II type 1 receptor (AT1 receptor) to stimulate the synthesis and release of aldosterone and promote cardiac stimulation. Angiotensin II promotes renal tubular reabsorption of sodium, resulting in water retention. It also inhibits further secretion of renin. AT1 receptors are highly expressed in vascular smooth muscle and the adrenal gland. Azilsartan medoxomil is a prodrug that is hydrolyzed to its active metabolite, azilsartan, in the gastrointestinal tract following oral administration. Azilsartan selectively binds to AT1 receptors as an antagonist, blocking vasoconstrictor and aldosterone-secreting effects of angiotensin II. Azilsartan has more than a 10,000-fold greater affinity for the AT1 receptor than for the AT2 receptor, which is predominantly involved in cardiovascular homeostasis. Azilsartan appears to dissociate from AT1 receptors much more slowly than other ARBs, which explains its longer duration of action when compared to other ARBs. •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): During absorption, azilsartan medoxomil is hydrolyzed to azilsartan. The parent drug is not detectable in plasma after oral administration. The absolute bioavailability of azilsartan is estimated to be 60%. T max ranges from 1.5 to three hours. Steady-state levels of azilsartan are achieved within five days, and no accumulation in plasma occurs with repeated once-daily dosing. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of azilsartan is approximately 16 L. In rats, a minimal amount of radiolabelled drug crossed the blood-brain barrier. Azilsartan crossed the placental barrier in pregnant rats and was distributed to the fetus. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Azilsartan is >99% bound to human plasma proteins, mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): After azilsartan medoxomil is hydrolyzed into its active metabolite, azilsartan is metabolized to two primary metabolites, which are pharmacologically inactive. The major metabolite in plasma is metabolite M-II, which is formed via O-dealkylation mediated by CYP2C9. The minor metabolite is metabolite M-I, which is formed via decarboxylation mediated by CYP2C8 and CYP2B6. MII has approximately 50% systemic exposure of azilsartan, and MI has less than 1% systemic exposure of azilsartan. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following oral administration of 14C-labeled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine. Of the recovered dose in urine, about 15% was excreted as azilsartan. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half-life of azilsartan is approximately 11 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 of azilsartan is approximately 2.3 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): No maximum toxic doses have been established yet for azilsartan. There is limited human data available related to azilsartan medoxomil overdosage. In clinical trials, healthy subjects tolerated once-daily doses up to 320 mg of azilsartan medoxomil well. In the event of drug overdose, supportive measures should be initiated as azilsartan is not dialyzable. Azilsartan is a teratogenic agent with a risk of congenital abnormalities. Azilsartan and other ARB drugs are considered fetotoxic during the second and third trimesters. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Edarbi, Edarbyclor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed