Safety and Tolerability of Tecarfarin (ATI-5923) in Healthy Chinese Volunteers: Multiple Oral Dose-Escalation Phase I Trial

Abstract

Background Tecarfarin (ATI-5923), a structural analog of warfarin, was designed to provide more uniform and stable anticoagulation. Objective We aimed to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tecarfarin when administered in multiple ascending doses (MADs) to healthy Chinese volunteers. Methods Forty healthy Chinese volunteers were enrolled into four sequential cohorts (10, 20, 30, and 40 mg), with 10 subjects in each cohort. Participants in the MAD study for each sequential cohort were dose-titrated to achieve the target international normalized ratio (INR 1.7-2.0) for 14 days. Safety and tolerability were assessed throughout the study. Results The pharmacokinetic and pharmacodynamic profile of tecarfarin was investigated in a healthy Chinese population. Dose titration of tecarfarin was necessary to keep the INR in the target range in all subjects in the 20, 30 and 40 mg cohorts and a few subjects (n = 3) in the 10 mg cohort. Tecarfarin was well tolerated without serious adverse events. Only one treatment-related adverse event (hematochezia) resulted in early withdrawal from the MAD 40 mg cohort. Conclusion Tecarfarin was well-tolerated by Chinese volunteers. Dose titration was needed for tecarfarin doses larger than 20 mg to keep the INR in the target range.