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Is there an interaction between Abaloparatide and Acebutolol?

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 Acebutololum Acetobutolol Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Acebutolol is a selective β1-receptor antagonist used for the management of hypertension and ventricular premature beats in adults.

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. The severity of the interaction is minor.

qa

What is the severity of the interaction when Abaloparatide and Acebutolol are co-administered?

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 Acebutololum Acetobutolol Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Acebutolol is a selective β1-receptor antagonist used for the management of hypertension and ventricular premature beats in adults.

Minor

classification

Can Abaloparatide and Aldesleukin be taken together?

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. The severity of the interaction is minor.

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How severe is the interaction between Abaloparatide and Aldesleukin?

Minor

classification

How do Abaloparatide and Aliskiren interact?

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 Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Aliskiren is a direct renin inhibitor used to manage hypertension.

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. The severity of the interaction is minor.

qa

Rate the interaction severity between Abaloparatide and Aliskiren.

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 Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Aliskiren is a direct renin inhibitor used to manage hypertension.

Minor

classification

Do Abaloparatide and Ambrisentan interact with each other?

The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

qa

What is the severity of the interaction when Abaloparatide and Ambrisentan are co-administered?

Minor

classification

Can Abaloparatide and Amifostine be taken together?

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. The severity of the interaction is minor.

qa

What is the risk level of combining Abaloparatide and Amifostine?

Minor

classification

Do Abaloparatide and Amiloride interact with each other?

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): Amilorid Amilorida Amiloride Amiloridum Amipramidin Amipramidine Amyloride Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Amiloride is a pyrizine compound used to treat hypertension and congestive heart failure.

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. The severity of the interaction is minor.

qa

What is the risk level of combining Abaloparatide and Amiloride?

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): Amilorid Amilorida Amiloride Amiloridum Amipramidin Amipramidine Amyloride Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Amiloride is a pyrizine compound used to treat hypertension and congestive heart failure.

Minor

classification

How do Abaloparatide and Amiodarone interact?

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. The severity of the interaction is minor.

qa

Rate the interaction severity between Abaloparatide and Amiodarone.

Minor

classification

Do Abaloparatide and Amlodipine interact with each other?

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. The severity of the interaction is minor.

qa

What is the severity of the interaction when Abaloparatide and Amlodipine are co-administered?

Minor

classification

Can Abaloparatide and Amobarbital be taken together?

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. The severity of the interaction is moderate.

qa

Rate the interaction severity between Abaloparatide and Amobarbital.

Minor

classification

Is there an interaction between Abaloparatide and Amphotericin B?

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. The severity of the interaction is minor.

qa

What is the risk level of combining Abaloparatide and Amphotericin B?

Minor

classification

Can Abaloparatide and Amyl Nitrite be taken together?

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. The severity of the interaction is minor.

qa

What is the severity of the interaction when Abaloparatide and Amyl Nitrite are co-administered?

Minor

classification

Can Abaloparatide and Apomorphine be taken together?

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. The severity of the interaction is minor.

qa

What is the severity of the interaction when Abaloparatide and Apomorphine are co-administered?

Minor

classification

Can Abaloparatide and Aripiprazole lauroxil be taken together?

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. The severity of the interaction is minor.

qa

What is the severity of the interaction when Abaloparatide and Aripiprazole lauroxil are co-administered?

Minor

classification

Can Abaloparatide and Aripiprazole be taken together?

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. The severity of the interaction is minor.

qa

What is the risk level of combining Abaloparatide and Aripiprazole?

Minor

classification

How do Abaloparatide and Arsenic trioxide interact?

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. The severity of the interaction is minor.

qa

What is the risk level of combining Abaloparatide and Arsenic trioxide?

Minor

classification

How do Abaloparatide and Atenolol interact?

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. The severity of the interaction is minor.

qa

How severe is the interaction between Abaloparatide and Atenolol?

Minor

classification

Do Abaloparatide and Avanafil interact with each other?

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. The severity of the interaction is minor.

qa

How severe is the interaction between Abaloparatide and Avanafil?

Minor

classification

Do Abaloparatide and Azilsartan medoxomil interact with each other?

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. The severity of the interaction is minor.

qa

Rate the interaction severity between Abaloparatide and Azilsartan medoxomil.

Minor

classification

Is there an interaction between Abaloparatide and Benazepril?

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. The severity of the interaction is minor.

qa

How severe is the interaction between Abaloparatide and Benazepril?

Minor

classification

Can Abaloparatide and Betaxolol be taken together?

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. The severity of the interaction is minor.

qa

What is the risk level of combining Abaloparatide and Betaxolol?

Minor

classification

How do Abaloparatide and Bisoprolol interact?

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. The severity of the interaction is minor.

qa

What is the risk level of combining Abaloparatide and Bisoprolol?

Minor

classification

How do Abaloparatide and Bosentan interact?

The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

qa

What is the severity of the interaction when Abaloparatide and Bosentan are co-administered?

Minor

classification

Do Abaloparatide and Bretylium interact with each other?

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. The severity of the interaction is minor.

qa

What is the severity of the interaction when Abaloparatide and Bretylium are co-administered?

Minor

classification

Can Abaloparatide and Bromocriptine be taken together?

Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. Indication (Drug B): For the treatment of galactorrhea due to hyperprolactinemia, prolactin-dependent menstrual disorders and infertility, prolactin-secreting adenomas, prolactin-dependent male hypogonadism, as adjunct therapy to surgery or radiotherapy for acromegaly or as monotherapy is special cases, as monotherapy in early Parksinsonian Syndrome or as an adjunct with levodopa in advanced cases with motor complications. Bromocriptine has also been used off-label to treat restless legs syndrome and neuroleptic malignant syndrome. Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. Pharmacodynamics (Drug B): Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D 1 and D 5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D 2, D 3 and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D 2 and D 3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D 2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D 2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D 2 -receptors. It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT) 1D, dopamine D 3, 5-HT 1A, 5-HT 2A, 5-HT 1B, and 5-HT 2C receptors, antagonist activity on α 2A -adrenergic, α 2C, α 2B, and dopamine D 1 receptors, partial agonist activity at receptor 5-HT 2B, and inactivates dopamine D 4 and 5-HT 7 receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT 2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion making bromocriptine an effective agent for treating disorders associated with hypersecretion of prolactin. Pulmonary fibrosis may be associated bromocriptine’s agonist activity at 5-HT 1B and 5-HT 2B receptors. Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. Mechanism of action (Drug B): The dopamine D 2 receptor is a 7-transmembrane G-protein coupled receptor associated with G i proteins. In lactotrophs, stimulation of dopamine D 2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D 2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders. 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 28% of the oral dose is absorbed; however due to a substantial first pass effect, only 6% of the oral dose reaches the systemic circulation unchanged. Bromocriptine and its metabolites appear in the blood as early as 10 minutes following oral administration and peak plasma concentration are reached within 1-1.5 hours. Serum prolactin may be decreased within 2 hours or oral administration with a maximal effect achieved after 8 hours. Growth hormone concentrations in patients with acromegaly is reduced within 1-2 hours with a single oral dose of 2.5 mg and decreased growth hormone concentrations persist for at least 4-5 hours. Volume of distribution (Drug A): The volume of distribution was approximately 50 L. Volume of distribution (Drug B): No volume of distribution available Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. Protein binding (Drug B): 90-96% bound to serum albumin Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. Metabolism (Drug B): Completely metabolized by the liver, primarily by hydrolysis of the amide bond to produce lysergic acid and a peptide fragment, both inactive and non-toxic. Bromocriptine is metabolized by cytochrome P450 3A4 and excreted primarily in the feces via biliary secretion. Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. Route of elimination (Drug B): Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney. Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. Half-life (Drug B): 2-8 hours Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. Clearance (Drug B): No clearance available Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. Toxicity (Drug B): Symptoms of overdosage include nausea, vomiting, and severe hypotension. The most common adverse effects include nausea, headache, vertigo, constipation, light-headedness, abdominal cramps, nasal congestion, diarrhea, and hypotension. Brand Names (Drug A): Tymlos Brand Names (Drug B): Cycloset, Parlodel Synonyms (Drug A): No synonyms listed Synonyms (Drug B): Bromocriptina Bromocriptine Bromocriptinum Bromocryptine Bromoergocriptine Bromoergocryptine Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Bromocriptine is a dopamine D2 receptor agonist used for the treatment of galactorrhea due to hyperprolactinemia and other prolactin-related conditions, as well as in early Parkinsonian Syndrome.

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. The severity of the interaction is minor.

qa

How severe is the interaction between Abaloparatide and Bromocriptine?

Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. Indication (Drug B): For the treatment of galactorrhea due to hyperprolactinemia, prolactin-dependent menstrual disorders and infertility, prolactin-secreting adenomas, prolactin-dependent male hypogonadism, as adjunct therapy to surgery or radiotherapy for acromegaly or as monotherapy is special cases, as monotherapy in early Parksinsonian Syndrome or as an adjunct with levodopa in advanced cases with motor complications. Bromocriptine has also been used off-label to treat restless legs syndrome and neuroleptic malignant syndrome. Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. Pharmacodynamics (Drug B): Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D 1 and D 5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D 2, D 3 and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D 2 and D 3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D 2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D 2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D 2 -receptors. It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT) 1D, dopamine D 3, 5-HT 1A, 5-HT 2A, 5-HT 1B, and 5-HT 2C receptors, antagonist activity on α 2A -adrenergic, α 2C, α 2B, and dopamine D 1 receptors, partial agonist activity at receptor 5-HT 2B, and inactivates dopamine D 4 and 5-HT 7 receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT 2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion making bromocriptine an effective agent for treating disorders associated with hypersecretion of prolactin. Pulmonary fibrosis may be associated bromocriptine’s agonist activity at 5-HT 1B and 5-HT 2B receptors. Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. Mechanism of action (Drug B): The dopamine D 2 receptor is a 7-transmembrane G-protein coupled receptor associated with G i proteins. In lactotrophs, stimulation of dopamine D 2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D 2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders. 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 28% of the oral dose is absorbed; however due to a substantial first pass effect, only 6% of the oral dose reaches the systemic circulation unchanged. Bromocriptine and its metabolites appear in the blood as early as 10 minutes following oral administration and peak plasma concentration are reached within 1-1.5 hours. Serum prolactin may be decreased within 2 hours or oral administration with a maximal effect achieved after 8 hours. Growth hormone concentrations in patients with acromegaly is reduced within 1-2 hours with a single oral dose of 2.5 mg and decreased growth hormone concentrations persist for at least 4-5 hours. Volume of distribution (Drug A): The volume of distribution was approximately 50 L. Volume of distribution (Drug B): No volume of distribution available Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. Protein binding (Drug B): 90-96% bound to serum albumin Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. Metabolism (Drug B): Completely metabolized by the liver, primarily by hydrolysis of the amide bond to produce lysergic acid and a peptide fragment, both inactive and non-toxic. Bromocriptine is metabolized by cytochrome P450 3A4 and excreted primarily in the feces via biliary secretion. Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. Route of elimination (Drug B): Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney. Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. Half-life (Drug B): 2-8 hours Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. Clearance (Drug B): No clearance available Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. Toxicity (Drug B): Symptoms of overdosage include nausea, vomiting, and severe hypotension. The most common adverse effects include nausea, headache, vertigo, constipation, light-headedness, abdominal cramps, nasal congestion, diarrhea, and hypotension. Brand Names (Drug A): Tymlos Brand Names (Drug B): Cycloset, Parlodel Synonyms (Drug A): No synonyms listed Synonyms (Drug B): Bromocriptina Bromocriptine Bromocriptinum Bromocryptine Bromoergocriptine Bromoergocryptine Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Bromocriptine is a dopamine D2 receptor agonist used for the treatment of galactorrhea due to hyperprolactinemia and other prolactin-related conditions, as well as in early Parkinsonian Syndrome.

Minor

classification

Is there an interaction between Abaloparatide and Bumetanide?

Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. Indication (Drug B): For the treatment of edema associated with congestive heart failure, hepatic and renal disease including the nephrotic syndrome. Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. Pharmacodynamics (Drug B): Bumetanide is a loop diuretic of the sulfamyl category to treat heart failure. It is often used in patients in whom high doses of furosemide are ineffective. There is however no reason not to use bumetanide as a first choice drug. The main difference between the two substances is in bioavailability. Bumetanide has more predictable pharmacokinetic properties as well as clinical effect. In patients with normal renal function, bumetanide is 40 times more effective than furosemide. 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): Bumetanide interferes with renal cAMP and/or inhibits the sodium-potassium ATPase pump. Bumetanide appears to block the active reabsorption of chloride and possibly sodium in the ascending loop of Henle, altering electrolyte transfer in the proximal tubule. This results in excretion of sodium, chloride, and water and, hence, diuresis. 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): Bumetanide is completely absorbed (80%), and the absorption is not altered when taken with food. Bioavailability is almost complete. 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): 97% Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. Metabolism (Drug B): 45% is secreted unchanged. Urinary and biliary metabolites are formed by oxidation of the N-butyl side chain. Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. Route of elimination (Drug B): Oral administration of carbon-14 labeled Bumex to human volunteers revealed that 81% of the administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Biliary excretion of Bumex amounted to only 2% of the administered dose. Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. Half-life (Drug B): 60-90 minutes Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. Clearance (Drug B): 0.2 - 1.1 mL/min/kg [preterm and full-term neonates with respiratory disorders] 2.17 mL/min/kg [neonates receiving bumetanide for volume overload] 1.8 +/- 0.3 mL/min/kg [geriatric subjects] 2.9 +/- 0.2 mL/min/kg [younger subjects] Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. Toxicity (Drug B): Overdosage can lead to acute profound water loss, volume and electrolyte depletion, dehydration, reduction of blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confusion, anorexia, lethargy, vomiting and cramps. Treatment consists of replacement of fluid and electrolyte losses by careful monitoring of the urine and electrolyte output and serum electrolyte levels. Brand Names (Drug A): Tymlos Brand Names (Drug B): Bumex, Burinex Synonyms (Drug A): No synonyms listed Synonyms (Drug B): Bumetanida Bumetanide Bumetanidum Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Bumetanide is a sulfamyl diuretic used to treat edema in congestive heart failure, hepatic and renal disease, and nephrotic syndrome.

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. The severity of the interaction is minor.

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What is the risk level of combining Abaloparatide and Bumetanide?

Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. Indication (Drug B): For the treatment of edema associated with congestive heart failure, hepatic and renal disease including the nephrotic syndrome. Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. Pharmacodynamics (Drug B): Bumetanide is a loop diuretic of the sulfamyl category to treat heart failure. It is often used in patients in whom high doses of furosemide are ineffective. There is however no reason not to use bumetanide as a first choice drug. The main difference between the two substances is in bioavailability. Bumetanide has more predictable pharmacokinetic properties as well as clinical effect. In patients with normal renal function, bumetanide is 40 times more effective than furosemide. 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): Bumetanide interferes with renal cAMP and/or inhibits the sodium-potassium ATPase pump. Bumetanide appears to block the active reabsorption of chloride and possibly sodium in the ascending loop of Henle, altering electrolyte transfer in the proximal tubule. This results in excretion of sodium, chloride, and water and, hence, diuresis. 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): Bumetanide is completely absorbed (80%), and the absorption is not altered when taken with food. Bioavailability is almost complete. 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): 97% Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. Metabolism (Drug B): 45% is secreted unchanged. Urinary and biliary metabolites are formed by oxidation of the N-butyl side chain. Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. Route of elimination (Drug B): Oral administration of carbon-14 labeled Bumex to human volunteers revealed that 81% of the administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Biliary excretion of Bumex amounted to only 2% of the administered dose. Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. Half-life (Drug B): 60-90 minutes Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. Clearance (Drug B): 0.2 - 1.1 mL/min/kg [preterm and full-term neonates with respiratory disorders] 2.17 mL/min/kg [neonates receiving bumetanide for volume overload] 1.8 +/- 0.3 mL/min/kg [geriatric subjects] 2.9 +/- 0.2 mL/min/kg [younger subjects] Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. Toxicity (Drug B): Overdosage can lead to acute profound water loss, volume and electrolyte depletion, dehydration, reduction of blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confusion, anorexia, lethargy, vomiting and cramps. Treatment consists of replacement of fluid and electrolyte losses by careful monitoring of the urine and electrolyte output and serum electrolyte levels. Brand Names (Drug A): Tymlos Brand Names (Drug B): Bumex, Burinex Synonyms (Drug A): No synonyms listed Synonyms (Drug B): Bumetanida Bumetanide Bumetanidum Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Bumetanide is a sulfamyl diuretic used to treat edema in congestive heart failure, hepatic and renal disease, and nephrotic syndrome.

Minor

classification

Can Abaloparatide and Bupivacaine be taken together?

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. The severity of the interaction is minor.

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What is the risk level of combining Abaloparatide and Bupivacaine?

Minor

classification

Is there an interaction between Abaloparatide and Canagliflozin?

Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. Indication (Drug B): This drug is used in conjunction with diet and exercise to increase glycemic control in adults diagnosed with type 2 diabetes mellitus. Another indication for canagliflozin is the prevention of major cardiovascular events (myocardial infarction, stroke, or death due to a cardiovascular cause) in patients with type 2 diabetes, as well as hospitalization for heart failure in patients with type 2 diabetes. In addition to the above, canagliflozin can be used to lower the risk of end-stage kidney disease and major increases in serum creatinine and cardiovascular death for patients with a combination of type 2 diabetes mellitus, diabetic nephropathy, and albuminuria. It is important to note that this drug is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. 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): This drug increases urinary glucose excretion and decreases the renal threshold for glucose (RTG) in a dose-dependent manner. The renal threshold is defined as the lowest level of blood glucose associated with the appearance of detectable glucose in the urine. The end result of canagliflozin administration is increased urinary excretion of glucose and less renal absorption of glucose, decreasing glucose concentration in the blood and improving glycemic control. A note on type 2 diabetes and cardiovascular disease The risk of cardiovascular events in diabetes type 2 is increased due to the damaging effects of diabetes on blood vessels and nerves in the cardiovascular system. In particular, there is a tendency for hyperglycemia to create pro-atherogenic (plaque forming) lesions in blood vessels, leading to various fatal and non-fatal events including stroke and myocardial infarction. Long-term glycemic control has been proven to be effective in the prevention of cardiovascular events such as myocardial infarction and stroke in patients with type 2 diabetes. 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 sodium-glucose co-transporter2 (SGLT2), is found in the proximal tubules of the kidney, and reabsorbs filtered glucose from the renal tubular lumen. Canagliflozin inhibits the SGLT2 co-transporter. This inhibition leads to lower reabsorption of filtered glucose into the body and decreases the renal threshold for glucose (RTG), leading to increased glucose excretion in the urine. 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 and steady-state The absolute oral bioavailability of canagliflozin, on average, is approximately 65%. Steady-state concentrations are achieved after 4 to 5 days of daily dose administration between the range of 100mg to 300mg. Effect of food on absorption Co-administration of a high-fat meal with canagliflozin exerted no appreciable effect on the pharmacokinetic parameters of canagliflozin. This drug may be administered without regard to food. Despite this, because of the potential of canagliflozin to decrease postprandial plasma glucose excretion due to prolonged intestinal glucose absorption, it is advisable to take this drug before the first meal of the day. Volume of distribution (Drug A): The volume of distribution was approximately 50 L. Volume of distribution (Drug B): This drug is extensively distributed throughout the body. On average, the volume of distribution of canagliflozin at steady state following a single intravenous dose in healthy patients was measured to be 83.5 L. Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. Protein binding (Drug B): Canagliflozin is mainly bound to albumin. The plasma protein binding of this drug is 99%. Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. Metabolism (Drug B): Canagliflozin is primarily metabolized by O-glucuronidation. It is mainly glucuronidated by UGT1A9 and UGT2B4 enzymes to two inactive O-glucuronide metabolites. The oxidative metabolism of canagliflozin by hepatic cytochrome enzyme CYP3A4 is negligible (about 7%) in humans. Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. Route of elimination (Drug B): After a single oral radiolabeled dose canagliflozin dose to healthy subjects, the following ratios of canagliflozin or metabolites were measured in the feces and urine: Feces 41.5% as the unchanged radiolabeled drug 7.0% as a hydroxylated metabolite 3.2% as an O-glucuronide metabolite Urine About 33% of the ingested radiolabled dose was measured in the urine, generally in the form of O-glucuronide metabolites. Less than 1% of the dose was found excreted as unchanged drug in urine. Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. Half-life (Drug B): In a clinical study, the terminal half-life of canagliflozin was 10.6 hours for the 100mg dose and 13.1 hours for the 300 mg dose. Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. Clearance (Drug B): In healthy subjects, canagliflozin clearance was approximately 192 mL/min after intravenous (IV) administration. The renal clearance of 100 mg and 300 mg doses of canagliflozin was measured to be in the range of 1.30 - 1.55 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): Overdose information If an overdose occurs, contact the Poison Control Center. Normal supportive measures should be taken, including the removal unabsorbed drug from the gastrointestinal tract, initiating clinical monitoring of the patient, and providing supportive treatment as deemed necessary. Canagliflozin has been removed in very small quantities after a 4-hour hemodialysis session. This drug is likely not dialyzable by peritoneal dialysis. Pregnancy and lactation Animal data has demonstrated that canagliflozin may cause adverse renal effects in a growing fetus. Data are insufficient at this time in determining a potential canagliflozin related risk for major birth defects or possible miscarriage in humans. There are known risks, however, of uncontrolled diabetes in pregnancy. Inform female patients taking canagliflozin of the potential risk, which is increased during the second and third trimesters. This drug is not recommended during nursing. Mutagenesis and carcinogenicity Canagliflozin was not found to be mutagenic in both metabolically activated and inactivated states in the Ames assay. Canagliflozin showed mutagenicity in laboratory mouse lymphoma assay, but only in the activated state. Canagliflozin was not found to be mutagenic in several in vivo assays performed on rats. The carcinogenic risk of canagliflozin was assessed in 2-year studies completed in both CD1 mice and Sprague-Dawley rats. Canagliflozin was not shown to increase tumor incidence in mouse models given doses less than or equal to 14 times the exposure from a typical 300 mg dose in humans. Despite these negative findings in mice, the incidence of several tumors increased in mice, including Leydig cell tumors, renal tubular adenomas, and adrenal pheochromocytomas. Brand Names (Drug A): Tymlos Brand Names (Drug B): Invokamet, Invokana Synonyms (Drug A): No synonyms listed Synonyms (Drug B): Canagliflozin Canagliflozina Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used to manage hyperglycemia in type 2 diabetes mellitus (DM). Also used to reduce the risk of major cardiovascular events in patients with established cardiovascular disease and type 2 DM.

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. The severity of the interaction is minor.

qa

Rate the interaction severity between Abaloparatide and Canagliflozin.

Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. Indication (Drug B): This drug is used in conjunction with diet and exercise to increase glycemic control in adults diagnosed with type 2 diabetes mellitus. Another indication for canagliflozin is the prevention of major cardiovascular events (myocardial infarction, stroke, or death due to a cardiovascular cause) in patients with type 2 diabetes, as well as hospitalization for heart failure in patients with type 2 diabetes. In addition to the above, canagliflozin can be used to lower the risk of end-stage kidney disease and major increases in serum creatinine and cardiovascular death for patients with a combination of type 2 diabetes mellitus, diabetic nephropathy, and albuminuria. It is important to note that this drug is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. 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): This drug increases urinary glucose excretion and decreases the renal threshold for glucose (RTG) in a dose-dependent manner. The renal threshold is defined as the lowest level of blood glucose associated with the appearance of detectable glucose in the urine. The end result of canagliflozin administration is increased urinary excretion of glucose and less renal absorption of glucose, decreasing glucose concentration in the blood and improving glycemic control. A note on type 2 diabetes and cardiovascular disease The risk of cardiovascular events in diabetes type 2 is increased due to the damaging effects of diabetes on blood vessels and nerves in the cardiovascular system. In particular, there is a tendency for hyperglycemia to create pro-atherogenic (plaque forming) lesions in blood vessels, leading to various fatal and non-fatal events including stroke and myocardial infarction. Long-term glycemic control has been proven to be effective in the prevention of cardiovascular events such as myocardial infarction and stroke in patients with type 2 diabetes. 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 sodium-glucose co-transporter2 (SGLT2), is found in the proximal tubules of the kidney, and reabsorbs filtered glucose from the renal tubular lumen. Canagliflozin inhibits the SGLT2 co-transporter. This inhibition leads to lower reabsorption of filtered glucose into the body and decreases the renal threshold for glucose (RTG), leading to increased glucose excretion in the urine. 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 and steady-state The absolute oral bioavailability of canagliflozin, on average, is approximately 65%. Steady-state concentrations are achieved after 4 to 5 days of daily dose administration between the range of 100mg to 300mg. Effect of food on absorption Co-administration of a high-fat meal with canagliflozin exerted no appreciable effect on the pharmacokinetic parameters of canagliflozin. This drug may be administered without regard to food. Despite this, because of the potential of canagliflozin to decrease postprandial plasma glucose excretion due to prolonged intestinal glucose absorption, it is advisable to take this drug before the first meal of the day. Volume of distribution (Drug A): The volume of distribution was approximately 50 L. Volume of distribution (Drug B): This drug is extensively distributed throughout the body. On average, the volume of distribution of canagliflozin at steady state following a single intravenous dose in healthy patients was measured to be 83.5 L. Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. Protein binding (Drug B): Canagliflozin is mainly bound to albumin. The plasma protein binding of this drug is 99%. Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. Metabolism (Drug B): Canagliflozin is primarily metabolized by O-glucuronidation. It is mainly glucuronidated by UGT1A9 and UGT2B4 enzymes to two inactive O-glucuronide metabolites. The oxidative metabolism of canagliflozin by hepatic cytochrome enzyme CYP3A4 is negligible (about 7%) in humans. Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. Route of elimination (Drug B): After a single oral radiolabeled dose canagliflozin dose to healthy subjects, the following ratios of canagliflozin or metabolites were measured in the feces and urine: Feces 41.5% as the unchanged radiolabeled drug 7.0% as a hydroxylated metabolite 3.2% as an O-glucuronide metabolite Urine About 33% of the ingested radiolabled dose was measured in the urine, generally in the form of O-glucuronide metabolites. Less than 1% of the dose was found excreted as unchanged drug in urine. Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. Half-life (Drug B): In a clinical study, the terminal half-life of canagliflozin was 10.6 hours for the 100mg dose and 13.1 hours for the 300 mg dose. Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. Clearance (Drug B): In healthy subjects, canagliflozin clearance was approximately 192 mL/min after intravenous (IV) administration. The renal clearance of 100 mg and 300 mg doses of canagliflozin was measured to be in the range of 1.30 - 1.55 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): Overdose information If an overdose occurs, contact the Poison Control Center. Normal supportive measures should be taken, including the removal unabsorbed drug from the gastrointestinal tract, initiating clinical monitoring of the patient, and providing supportive treatment as deemed necessary. Canagliflozin has been removed in very small quantities after a 4-hour hemodialysis session. This drug is likely not dialyzable by peritoneal dialysis. Pregnancy and lactation Animal data has demonstrated that canagliflozin may cause adverse renal effects in a growing fetus. Data are insufficient at this time in determining a potential canagliflozin related risk for major birth defects or possible miscarriage in humans. There are known risks, however, of uncontrolled diabetes in pregnancy. Inform female patients taking canagliflozin of the potential risk, which is increased during the second and third trimesters. This drug is not recommended during nursing. Mutagenesis and carcinogenicity Canagliflozin was not found to be mutagenic in both metabolically activated and inactivated states in the Ames assay. Canagliflozin showed mutagenicity in laboratory mouse lymphoma assay, but only in the activated state. Canagliflozin was not found to be mutagenic in several in vivo assays performed on rats. The carcinogenic risk of canagliflozin was assessed in 2-year studies completed in both CD1 mice and Sprague-Dawley rats. Canagliflozin was not shown to increase tumor incidence in mouse models given doses less than or equal to 14 times the exposure from a typical 300 mg dose in humans. Despite these negative findings in mice, the incidence of several tumors increased in mice, including Leydig cell tumors, renal tubular adenomas, and adrenal pheochromocytomas. Brand Names (Drug A): Tymlos Brand Names (Drug B): Invokamet, Invokana Synonyms (Drug A): No synonyms listed Synonyms (Drug B): Canagliflozin Canagliflozina Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used to manage hyperglycemia in type 2 diabetes mellitus (DM). Also used to reduce the risk of major cardiovascular events in patients with established cardiovascular disease and type 2 DM.

Minor

classification

Is there an interaction between Abaloparatide and Candesartan cilexetil?

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. The severity of the interaction is minor.

qa

What is the risk level of combining Abaloparatide and Candesartan cilexetil?

Minor

classification

Is there an interaction between Abaloparatide and Captopril?

Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. Indication (Drug B): For the treatment of essential or renovascular hypertension (usually administered with other drugs, particularly thiazide diuretics). May be used to treat congestive heart failure in combination with other drugs (e.g. cardiac glycosides, diuretics, β-adrenergic blockers). May improve survival in patients with left ventricular dysfunction following myocardial infarction. May be used to treat nephropathy, including diabetic nephropathy. Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. Pharmacodynamics (Drug B): Captopril, an ACE inhibitor, antagonizes the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain its effects by causing increased vasodilation and decreased blood pressure. Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. Mechanism of action (Drug B): There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Captopril, one of the few ACE inhibitors that is not a prodrug, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Captopril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors. Captopril’s affinity for ACE is approximately 30,000 times greater than that of ATI. Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. Absorption (Drug B): 60-75% in fasting individuals; food decreases absorption by 25-40% (some evidence indicates that this is not clinically significant) 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): 25-30% bound to plasma proteins, primarily albumin Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. Metabolism (Drug B): Hepatic. Major metabolites are captopril-cysteine disulfide and the disulfide dimer of captopril. Metabolites may undergo reversible interconversion. 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): 2 hours Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. Clearance (Drug B): No clearance available Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. Toxicity (Drug B): Symptoms of overdose include emesis and decreased blood pressure. Side effects include dose-dependent rash (usually maculopapular), taste alterations, hypotension, gastric irritation, cough, and angioedema. Brand Names (Drug A): Tymlos Brand Names (Drug B): No brand names available Synonyms (Drug A): No synonyms listed Synonyms (Drug B): Captopril Captoprilum Captopryl L-Captopril Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Captopril is an ACE inhibitor used for the management of essential or renovascular hypertension, congestive heart failure, left ventricular dysfunction following myocardial infarction, and nephropathy.

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. The severity of the interaction is minor.

qa

How severe is the interaction between Abaloparatide and Captopril?

Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. Indication (Drug B): For the treatment of essential or renovascular hypertension (usually administered with other drugs, particularly thiazide diuretics). May be used to treat congestive heart failure in combination with other drugs (e.g. cardiac glycosides, diuretics, β-adrenergic blockers). May improve survival in patients with left ventricular dysfunction following myocardial infarction. May be used to treat nephropathy, including diabetic nephropathy. Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. Pharmacodynamics (Drug B): Captopril, an ACE inhibitor, antagonizes the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain its effects by causing increased vasodilation and decreased blood pressure. Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. Mechanism of action (Drug B): There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Captopril, one of the few ACE inhibitors that is not a prodrug, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Captopril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors. Captopril’s affinity for ACE is approximately 30,000 times greater than that of ATI. Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. Absorption (Drug B): 60-75% in fasting individuals; food decreases absorption by 25-40% (some evidence indicates that this is not clinically significant) 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): 25-30% bound to plasma proteins, primarily albumin Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. Metabolism (Drug B): Hepatic. Major metabolites are captopril-cysteine disulfide and the disulfide dimer of captopril. Metabolites may undergo reversible interconversion. 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): 2 hours Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. Clearance (Drug B): No clearance available Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. Toxicity (Drug B): Symptoms of overdose include emesis and decreased blood pressure. Side effects include dose-dependent rash (usually maculopapular), taste alterations, hypotension, gastric irritation, cough, and angioedema. Brand Names (Drug A): Tymlos Brand Names (Drug B): No brand names available Synonyms (Drug A): No synonyms listed Synonyms (Drug B): Captopril Captoprilum Captopryl L-Captopril Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Captopril is an ACE inhibitor used for the management of essential or renovascular hypertension, congestive heart failure, left ventricular dysfunction following myocardial infarction, and nephropathy.

Minor

classification

Is there an interaction between Abaloparatide and Carbetocin?

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. The severity of the interaction is minor.

qa

What is the severity of the interaction when Abaloparatide and Carbetocin are co-administered?

Minor

classification

Do Abaloparatide and Carvedilol interact with each other?

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. The severity of the interaction is minor.

qa

How severe is the interaction between Abaloparatide and Carvedilol?

Minor

classification

Do Abaloparatide and Celiprolol interact with each other?

The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

qa

Rate the interaction severity between Abaloparatide and Celiprolol.

Minor

classification

Do Abaloparatide and Chlorothiazide interact with each other?

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. The severity of the interaction is minor.

qa

Rate the interaction severity between Abaloparatide and Chlorothiazide.

Minor

classification

Do Abaloparatide and Chlorpromazine interact with each other?

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. The severity of the interaction is minor.

qa

What is the risk level of combining Abaloparatide and Chlorpromazine?

Minor

classification

How do Abaloparatide and Chlorthalidone interact?

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. The severity of the interaction is minor.

qa

What is the severity of the interaction when Abaloparatide and Chlorthalidone are co-administered?

Minor

classification

Can Abaloparatide and Cilazapril be taken together?

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. The severity of the interaction is minor.

qa

What is the severity of the interaction when Abaloparatide and Cilazapril are co-administered?

Minor

classification

Is there an interaction between Abaloparatide and Clevidipine?

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 reduction of blood pressure when when oral antihypertensive therapy is not feasible or not desirable. 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): Clevidipine belongs to a well-known class of drugs called dihydropyridine calcium channel antagonists. Clevidpine is the first third generation intravenous dihydropyridine calcium channel blocker. In vitro studies demonstrated that clevidipine acts by selectively relaxing the smooth muscle cells that line small arteries, resulting in arterial dilation, widening of the artery opening, and without reducing central venous pressure or reducing cardiac output. 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): Possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, clevidipine inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue. Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. Absorption (Drug B): No absorption available Volume of distribution (Drug A): The volume of distribution was approximately 50 L. Volume of distribution (Drug B): No volume of distribution available Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. Protein binding (Drug B): >99.5% Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. Metabolism (Drug B): Clevidipine is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. Route of elimination (Drug B): urine 63-74%, feces 7-22% Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. Half-life (Drug B): 1 minute 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): Cleviprex Synonyms (Drug A): No synonyms listed Synonyms (Drug B): No synonyms listed Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Clevidipine is a dihydropyridine L-type calcium channel blocker used to lower blood pressure when oral antihypertensive therapy is not feasible or not desirable.

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. The severity of the interaction is minor.

qa

What is the severity of the interaction when Abaloparatide and Clevidipine are co-administered?

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 reduction of blood pressure when when oral antihypertensive therapy is not feasible or not desirable. 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): Clevidipine belongs to a well-known class of drugs called dihydropyridine calcium channel antagonists. Clevidpine is the first third generation intravenous dihydropyridine calcium channel blocker. In vitro studies demonstrated that clevidipine acts by selectively relaxing the smooth muscle cells that line small arteries, resulting in arterial dilation, widening of the artery opening, and without reducing central venous pressure or reducing cardiac output. 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): Possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, clevidipine inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue. Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. Absorption (Drug B): No absorption available Volume of distribution (Drug A): The volume of distribution was approximately 50 L. Volume of distribution (Drug B): No volume of distribution available Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. Protein binding (Drug B): >99.5% Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. Metabolism (Drug B): Clevidipine is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. Route of elimination (Drug B): urine 63-74%, feces 7-22% Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. Half-life (Drug B): 1 minute 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): Cleviprex Synonyms (Drug A): No synonyms listed Synonyms (Drug B): No synonyms listed Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Clevidipine is a dihydropyridine L-type calcium channel blocker used to lower blood pressure when oral antihypertensive therapy is not feasible or not desirable.

Minor

classification

Can Abaloparatide and Clofarabine be taken together?

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. The severity of the interaction is minor.

qa

What is the severity of the interaction when Abaloparatide and Clofarabine are co-administered?

Minor

classification

Is there an interaction between Abaloparatide and Clomipramine?

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): May be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette’s disorder). Unlabeled indications include: depression, panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy (limited evidence), autistic disorder (limited evidence), trichotillomania (limited evidence), onchophagia (limited evidence), stuttering (limited evidence), premature ejaculation, and premenstrual syndrome. Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. Pharmacodynamics (Drug B): Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine. It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: α 1 and β 1 receptors are sensitized, α 2 receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. 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): Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α 1 -receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type. 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 GI tract following oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food. Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL). There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism. On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration. Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine. Volume of distribution (Drug A): The volume of distribution was approximately 50 L. Volume of distribution (Drug B): ~ 17 L/kg (range: 9-25 L/kg). Clomipramine is capable of distributing into the cerebrospinal fluid, the brain, and into breast milk. Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. Protein binding (Drug B): Clomipramine is approximately 97-98% bound to plasma proteins, principally to albumin and possibly to α 1 -acid glycoprotein. Desmethylclomipramine is 97-99% bound to plasma proteins. Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. Metabolism (Drug B): Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by N -demethylation of clomipramine via CYP2C19, 3A4 and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine N -oxide formed by N -oxidation. Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and N -demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical relevance remains unknown. Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. Route of elimination (Drug B): Urine (51-60%) and feces via biliary elimination (24-32%) Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. Half-life (Drug B): Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism). Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. Clearance (Drug B): No clearance available Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. Toxicity (Drug B): Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia. Brand Names (Drug A): Tymlos Brand Names (Drug B): Anafranil Synonyms (Drug A): No synonyms listed Synonyms (Drug B): 3-Chloroimipramine Chlorimipramine Clomipramina Clomipramine Clomipraminum Monochlorimipramine Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Clomipramine is a tricyclic antidepressant used in the treatment of obsessive-compulsive disorder and disorders with an obsessive-compulsive component, such as depression, schizophrenia, and Tourette’s disorder.

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. The severity of the interaction is minor.

qa

How severe is the interaction between Abaloparatide and Clomipramine?

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): May be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette’s disorder). Unlabeled indications include: depression, panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy (limited evidence), autistic disorder (limited evidence), trichotillomania (limited evidence), onchophagia (limited evidence), stuttering (limited evidence), premature ejaculation, and premenstrual syndrome. Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. Pharmacodynamics (Drug B): Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine. It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: α 1 and β 1 receptors are sensitized, α 2 receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. 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): Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α 1 -receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type. 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 GI tract following oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food. Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL). There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism. On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration. Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine. Volume of distribution (Drug A): The volume of distribution was approximately 50 L. Volume of distribution (Drug B): ~ 17 L/kg (range: 9-25 L/kg). Clomipramine is capable of distributing into the cerebrospinal fluid, the brain, and into breast milk. Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. Protein binding (Drug B): Clomipramine is approximately 97-98% bound to plasma proteins, principally to albumin and possibly to α 1 -acid glycoprotein. Desmethylclomipramine is 97-99% bound to plasma proteins. Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. Metabolism (Drug B): Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by N -demethylation of clomipramine via CYP2C19, 3A4 and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine N -oxide formed by N -oxidation. Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and N -demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical relevance remains unknown. Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. Route of elimination (Drug B): Urine (51-60%) and feces via biliary elimination (24-32%) Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. Half-life (Drug B): Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism). Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. Clearance (Drug B): No clearance available Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. Toxicity (Drug B): Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia. Brand Names (Drug A): Tymlos Brand Names (Drug B): Anafranil Synonyms (Drug A): No synonyms listed Synonyms (Drug B): 3-Chloroimipramine Chlorimipramine Clomipramina Clomipramine Clomipraminum Monochlorimipramine Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. Summary (Drug B): Clomipramine is a tricyclic antidepressant used in the treatment of obsessive-compulsive disorder and disorders with an obsessive-compulsive component, such as depression, schizophrenia, and Tourette’s disorder.

Minor

classification

Can Abaloparatide and Clonidine be taken together?

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. The severity of the interaction is minor.

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Rate the interaction severity between Abaloparatide and Clonidine.

Minor

classification