Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of apixaban in healthy Japanese male subjects

摘要

This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study to assess the safety, tolerability, pharmacokinetics, and phannacodynamics of multiple oral doses of apixaban in healthy Japanese male subjects. Methods: The study was conducted using three sequential dose panels: Apixaban 2.5 mg, 5 mg, and 10 mg given twice daily. For each dose panel, subjects were randomly assigned to receive oral apixaban (n = 6) or matching placebo (n = 2) for 7 days. The pharmacokinetics of apixaban and effect on pharmacodynamic variables (clotting assays and anti-Xa activity) were assessed on day 1 and day 7 of treatment. Safety was assessed throughout the study. Only after the preceding dose was con- finned to be safe and well- Tolerated subjects were enrolled into the next-higher-dose panel. Results: Apixaban was safe and well- Tolerated in these healthy Japanese male subjects across the doses evaluated. On day 7, peak plasma concentrations were reached ~ 3 hours post- dose, and increases in peak plasma concentration (Cmax), trough plasma concentration, and area under the plasma concentration- Time curve across one dosing interval (12 hours) were tested dose-proportional across the dose range. A modest degree of accumulation was observed that was similar for all doses (accumulation index of 1.7 to 2.0), and renal clearance was consistent across doses (0.91 L/h - 1.07 L/h). Exposure-dependent prolongation of prothrombin time, activated partial thromboplastin time, modified prothrombin time, and increases in anti-Xa activity were observed after single and multiple doses of apixaban. Conclusions: Apixaban was safe and well- Tolerated in healthy Japanese sub-jects. The pharmacokinetic profile of apixaban following multiple twice-daily doses was linear, and exposure parameters such as Cmax, observed at ~ 3 hours post-dose, and area under the plasma concentration- Time curve increased in a dose-proportional manner. Phar macodynamic profiles closely followed the apixaban plasma concentration- Time profiles.