Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects

摘要

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT ? Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. ? In single- and multiple-dose Phase I studies in White subjects, rivaroxaban was safe and demonstrated predictable, dose-dependent pharmacokinetics and pharmacodynamics. WHAT THIS STUDY ADDS ? The Phase III programme with rivaroxaban is being conducted worldwide. ? Therefore, it is necessary to determine whether the pharmacokinetics, pharmacodynamics and tolerability of rivaroxaban are altered in patients of different ethnic origins. ? Dose-escalation studies were conducted to determine the safety, pharmacokinetics and pharmacodynamics of single and multiple doses of rivaroxaban in healthy Chinese subjects. AIMS To investigate the safety, pharmacokinetics and pharmacodynamics of rivaroxaban, an oral, direct Factor Xa (FXa) inhibitor, in healthy, male Chinese subjects. METHODS Two randomized, single-blind, placebo-controlled, dose-escalation studies were conducted in healthy Chinese men aged 18–45 years. In the single-dose study, subjects received single, oral doses of rivaroxaban 2.5, 5, 10, 20 and 40 mg. In the multiple-dose study, oral rivaroxaban was administered in doses of 5, 10, 20 and 30 mg twice daily for 6 days. RESULTS Rivaroxaban, in single and multiple doses up to 60 mg, was well tolerated. Rapid absorption was observed in both studies (time to C _max 1.25–2.5 h). In the multiple-dose study, rivaroxaban exposure increased dose-proportionally after the first dose and at steady state (for the 5–20-mg doses). The half-life of rivaroxaban was up to 7.9 h in the single-dose study. Maximal inhibition of FXa activity was achieved within 1–3 h of dosing in the single-dose study [at 20 mg FXa inhibition as a median percentage change from baseline, 45.92; 95% confidence interval (CI) 44.64, 50.70] and 2–3 h after administration at steady state in the multiple-dose study (at 20 mg median FXa inhibition as a median percentage change from baseline, 60.25; 95% CI 56.16, 63.05), in line with maximum rivaroxaban plasma concentrations. CONCLUSIONS Rivaroxaban demonstrated predictable pharmacokinetics and pharmacodynamics in healthy Chinese subjects, in line with findings observed previously in White subjects. This suggests that fixed doses of rivaroxaban may be administered to all patients, regardless of their ethnic origin.