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.
Galcanezumab, a humanized monoclonal calcitonin gene-related peptide (CGRP) antibody, is being developed for cluster headache and migraine prevention. This study evaluated galcanezumab safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy Japanese and Caucasian subjects. Galcanezumab or placebo was administered as subcutaneous injections to 4 singledose cohorts (5, 50, 120, 300 mg) and 1 multiple-dose cohort (3 consecutive, 300-mg doses, every 4 weeks). Safety measurements included treatment-emergent adverse events (TEAEs), vital signs, electrocardiograms, clinical laboratory tests, and anti-drug antibodies (ADA). Blood samples were analyzed for serum galcanezumab and plasma CGRP concentrations.
Twenty-five Japanese and twenty Caucasians, 22 to 63 years of age, were enrolled; 27 received a single dose (N＝6 to 8 per dose level), 8 received multiple doses, and 10 received placebo (8 single dose, 2 multiple dose). Forty-one subjects completed the study (24 single dose, 7 multiple dose, 10 placebo). Galcanezumab was well tolerated in Japanese and Caucasian subjects. There were no apparent dose-related increases in TEAEs or changes in vital signs, electrocardiogram parameters, laboratory values, or treatment-emergent ADA. Following single and multiple doses, maximum galcanezumab concentrations were observed approximately 5 to 9 days postdose and mean half-life was about 3 to 4 weeks. Increases in area under the concentration-time curve and maximum observed concentration were dose proportional. Galcanezumab pharmacokinetics and pharmacodynamics were similar between Japanese and Caucasian subjects. Plasma CGRP concentrations increased following galcanezumab administration consistent with CGRP (target) binding to galcanezumab (antibody). These data support further development of galcanezumab in Japanese patients.