Reventa Mechanism of Action

Pharmacology: Mechanism of Action: At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment but it does inhibit osteoclast activity. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces.
Pharmacokinetics: Absorption: Like other bisphosphonates, alendronate is poorly absorbed following oral administration. Absorption is decreased by food especially by products containing calcium or other polyvalent cations. Bioavailability is about 0.4% when administered ½ hr before food, reduced from 0.7% in the fasting state; absorption is negligible when taken up to 2 hrs after a meal.
Distribution: The mean steady-state volume of distribution, exclusive of the bone, is at least 28 L in humans. Concentrations of the drug in plasma following therapeutic oral doses are too low (<5 ng/mL) for analytical detection. Protein-binding in human plasma is approximately 78%.
Metabolism: There is no evidence that alendronate is metabolized in animals or humans.
Elimination: About ½ of the absorbed portion is excreted in the urine; the remainder is sequestered to bone for a prolonged period. The terminal t_½ in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton.
Special Populations: Pediatric: Alendronate pharmacokinetics have not been studied in patients <18 years.
Geriatric: Bioavailability and urinary excretion are similar in elderly (>60 years) and younger subjects. No dosage adjustment is necessary.
Renal Insufficiency: No dosage adjustment is necessary for patients with mild to moderate renal insufficiency (creatinine clearance 35-60 mL/min). Alendronate is not recommended in patients with severe renal impairment.
Hepatic Insufficiency: As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic insufficiency. No dosage adjustment is necessary.
Drug-Drug Relationship: Ranitidine: Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increase will occur in patients given oral H₂-antagonists is unknown.
Prednisone: Prednisone (20 mg 3 times daily for 5 days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (mean increase ranging from 20-44%).