Optimizing a Single Monthly Dose of Risedronate Based on its Weekly Dose in Healthy Japanese Postmenopausal Women

Abstract

Background and objectives: Risedronate is an anti-resorptive agent commonly used for the treatment of osteoporosis. This study investigated the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of risedronate to optimize the monthly dose in healthy Japanese postmenopausal women.
Methods: In this single-center, double-blinded, placebo-controlled study, subjects were randomized to receive risedronate (n＝8 per dose regimen) or placebo (n＝2 per dose regimen). Dosing regimens were either weekly dose of 17.5 mg for 4 consecutive wks, or single monthly dose (50, 75, 100, 125, or 150 mg). Safety was assessed by monitoring adverse events (AEs) and laboratory parameters. Dose proportionality was assessed using power model. PD analysis was performed using bone turnover markers (BTMs) and PK/PD analysis was performed using nonlinear mixed effect model.
Results: Out of 40 enrolled subjects, 38 completed the study. Administration of the monthly doses of 125 and 150 mg were cancelled. AEs were reported by 26/32 (81%) subjects (5 subjects in 17.5 mg group, 6 subjects in 50 mg group, 7 subjects in 75 mg group, and 8 subjects in 100 mg group) who received risedronate, however, most of AEs were mild. Dose over proportionality was implied for tested PK parameters. No obvious difference was observed between 75 and 100 mg administration for AUEC of BTMs. The final PK/PD model predicted that both uNTX/Cr and uCTX/Cr levels were similarly reduced with 75 mg monthly dose and 17.5 mg weekly dose.
Conclusion: Oral risedronate in the monthly doses of 50, 75 and 100 mg was found to be safe and well tolerated. PK and PD analyses suggested 75 mg monthly dose has comparable PD effects to 17.5 mg weekly dose.