Clinical Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Darexaban, an Oral Direct Factor Xa Inhibitor, in Healthy Elderly Japanese Subjects

Abstract

The clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban after single and multiple once-daily doses of 60, 120, and 240 mg in healthy elderly Japanese subjects were assessed. Following oral administration, darexaban was rapidly and extensively metabolized to darexaban glucuronide, which is an active glucuronide metabolite. Plasma concentrations of darexaban glucuronide increased with dose, and Cmax and AUC increased dose-dependently after both single and repeated doses. Cumulative urinary excretion of darexaban glucuronide up to 24 hours after repeated doses ranged from 28.59% to 36.50%. PT-INR, aPTT, and FXa activity were prolonged or decreased dose-dependently after both single and repeated doses of darexaban. The time-profile of pharamcodynamic parameters closely followed the time-concentration profile of darexaban glucuronide. Five adverse events occurred in the present study (4: darexaban [16.7%]; 1: placebo [8.3%]), all of which were mild in severity and required no treatment.