Clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban, an oral direct factor Xa inhibitor, in healthy Caucasian and Japanese subjects

BACKGROUND: Darexaban (YM150) is a potent direct factor Xa (FXa) inhibitor developed for the prophylaxis of venous and arterial thromboembolic disease. This drug is rapidly and extensively metabolized to darexaban glucuronide (YM-222714), which is a pharmacologically active metabolite. The objective of the present study was to evaluate the clinical pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of ascending multiple oral doses of darexaban in healthy non-elderly Caucasian and Japanese subjects. METHODS: A randomized, double-blind, placebo-controlled, single and multiple dose-escalating study of healthy Caucasian and Japanese male and female subjects was performed. The tested doses were 20, 60, 120 and 240 mg of darexaban. RESULTS: Plasma concentrations of darexaban glucuronide increased with dose, and Cmax and AUC increased dose-dependently after both single and repeated doses in both Caucasians and Japanese. Cmax was about 17%-19% lower in Caucasians than in Japanese, although AUC appeared to be similar. The time-profiles of prothrombin time reported as the international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT) and FXa activity closely followed the time-concentration profile of darexaban glucuronide, and no clear differences were observed in ethnicity. Overall, 38 of the 82 enrolled subjects reported a total of 57 treatment-emergent adverse events (TEAEs). Fifty-five TEAEs were of mild intensity and two were of moderate intensity. CONCLUSION: It is concluded that single and multiple doses of darexaban are safe and well tolerated up to 240 mg with predictable PK and PD profiles in both Caucasians and Japanese, and that ethnicity does not affect its PK, PD or tolerability.