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How do Abaloparatide and Methyldopa 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.

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What is the risk level of combining Abaloparatide and Methyldopa?

Minor

classification

Do Abaloparatide and Methylene blue interact with each other?

Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. The severity of the interaction is moderate.

qa

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

Minor

classification

How do Abaloparatide and Metolazone 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 Metolazone.

Minor

classification

Is there an interaction between Abaloparatide and Metoprolol?

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

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

Minor

classification

Is there an interaction between Abaloparatide and Metyrosine?

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

How severe is the interaction between Abaloparatide and Metyrosine?

Minor

classification

Do Abaloparatide and Minoxidil 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 Minoxidil?

Minor

classification

Can Abaloparatide and Moclobemide be taken together?

Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. The severity of the interaction is moderate.

qa

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

Minor

classification

Is there an interaction between Abaloparatide and Moexipril?

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

What is the risk level of combining Abaloparatide and Moexipril?

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

Minor

classification

Do Abaloparatide and Morphine 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 Morphine.

Minor

classification

Do Abaloparatide and Moxonidine 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 Moxonidine are co-administered?

Minor

classification

Can Abaloparatide and Nabilone 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 Nabilone are co-administered?

Minor

classification

Is there an interaction between Abaloparatide and Nadolol?

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

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

Minor

classification

Is there an interaction between Abaloparatide and Nebivolol?

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 Nebivolol.

Minor

classification

Do Abaloparatide and Nicardipine 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 Nicardipine?

Minor

classification

How do Abaloparatide and Nicorandil interact?

Nicorandil is an agent that induces the relaxation of vascular smooth muscle, and is associated with a risk for developing severe hypotension as an adverse event. There is also the possibility that nicorandil may potentiate the hypotensive effects of other vasodilators. The severity of the interaction is minor.

qa

Rate the interaction severity between Abaloparatide and Nicorandil.

Minor

classification

Is there an interaction between Abaloparatide and Nifedipine?

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 Nifedipine.

Minor

classification

Do Abaloparatide and Nilvadipine 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 Nilvadipine are co-administered?

Minor

classification

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

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 Nimodipine.

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

Minor

classification

How do Abaloparatide and Nisoldipine 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 Nisoldipine?

Minor

classification

Is there an interaction between Abaloparatide and Nitrendipine?

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 Nitrendipine?

Minor

classification

Can Abaloparatide and Nitric Oxide 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

Rate the interaction severity between Abaloparatide and Nitric Oxide.

Minor

classification

Do Abaloparatide and Nitroglycerin 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 Nitroglycerin.

Minor

classification

How do Abaloparatide and Nitroprusside 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 Nitroprusside.

Minor

classification

Can Abaloparatide and Nitrous acid 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

How severe is the interaction between Abaloparatide and Nitrous acid?

Minor

classification

Can Abaloparatide and Obinutuzumab 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

Rate the interaction severity between Abaloparatide and Obinutuzumab.

Minor

classification

Is there an interaction between Abaloparatide and Olanzapine?

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 Olanzapine.

Minor

classification

How do Abaloparatide and Olmesartan 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 Olmesartan are co-administered?

Minor

classification

Is there an interaction between Abaloparatide and Opicapone?

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 Opicapone?

Minor

classification

Is there an interaction between Abaloparatide and Paclitaxel?

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

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 Paclitaxel?

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

Minor

classification

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

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 Papaverine.

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

Minor

classification

Do Abaloparatide and Penbutolol 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 Penbutolol.

Minor

classification

How do Abaloparatide and Pentobarbital interact?

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 Pentobarbital.

Minor

classification

How do Abaloparatide and Perindopril 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 Perindopril.

Minor

classification

Do Abaloparatide and Phenelzine interact with each other?

Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. The severity of the interaction is moderate.

qa

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

Minor

classification

How do Abaloparatide and Phenobarbital interact?

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 Phenobarbital.

Minor

classification

Do Abaloparatide and Phenoxybenzamine 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 Phenoxybenzamine?

Minor

classification

How do Abaloparatide and Phentolamine 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 Phentolamine?

Minor

classification

Is there an interaction between Abaloparatide and Pindolol?

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

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

Minor

classification

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

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.

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How severe is the interaction between Abaloparatide and Polythiazide?

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

Minor

classification

Can Abaloparatide and Pramipexole 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 Pramipexole?

Minor

classification

Can Abaloparatide and Prazosin 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 severity of the interaction when Abaloparatide and Prazosin are co-administered?

Minor

classification

Can Abaloparatide and Primidone 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.

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How severe is the interaction between Abaloparatide and Primidone?

Minor

classification

Is there an interaction between Abaloparatide and Procaine?

Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. The severity of the interaction is moderate.

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How severe is the interaction between Abaloparatide and Procaine?

Minor

classification

Is there an interaction between Abaloparatide and Procarbazine?

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

Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. The severity of the interaction is moderate.

qa

What is the risk level of combining Abaloparatide and Procarbazine?

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

Minor

classification

Can Abaloparatide and Propofol 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

Rate the interaction severity between Abaloparatide and Propofol.

Minor

classification

Can Abaloparatide and Propranolol 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 Propranolol are co-administered?

Minor

classification

How do Abaloparatide and Quetiapine 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 Quetiapine are co-administered?

Minor

classification

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

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 Quinapril?

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

Minor

classification

Can Abaloparatide and Ramipril 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 Ramipril?

Minor

classification

Is there an interaction between Abaloparatide and Rasagiline?

Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. The severity of the interaction is moderate.

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How severe is the interaction between Abaloparatide and Rasagiline?

Minor

classification