Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939 - an oral, direct Factor Xa inhibitor - after multiple dosing in healthy male subjects

Objectives: There is a clinical need for safe new oral anticoagulants. The safety, tolerability, pharmacodynamics, and pharmacokinetics of BAY 59-7939 - a novel, oral, direct Factor Xa (FXa) inhibitor - were investigated in this single-center, placebo-controlled, single-blind, parallel-group, multiple-dose escalation study. Methods: Healthy male subjects ( aged 20 - 45 years, body mass index 18.6 - 31.4 kg/m(2)) received oral BAY 59-7939 ( n=8 per dose regimen) or placebo ( n=4 per dose regimen) on days 0 and 3 - 7. Dosing regimens were 5 mg once, twice ( bid), or three times daily, and 10 mg, 20 mg, or 30 mg bid. Results: There were no clinically relevant changes in bleeding time or other safety variables across all doses and regimens. There was no dose-related increase in the frequency or severity of adverse events with BAY 59-7939. Maximum inhibition of FXa activity occurred after approximately 3 h, and inhibition was maintained for at least 12 h for all doses. Prothrombin time, activated partial thromboplastin time, and HepTest were prolonged to a similar extent to inhibition of FXa activity for all doses. Dose-proportional pharmacokinetics (AUC(tau, norm) and C-max,C- norm) were observed at steady state ( day 7). Maximum plasma concentrations were achieved after 3 - 4 h. The terminal half-life of BAY 59-7939 was 5.7-9.2 h at steady state. There was no relevant accumulation at any dose. Conclusions: BAY 59-7939 was safe and well tolerated across the wide dose range studied, with predictable, dose-proportional pharmacokinetics and pharmacodynamics and no relevant accumulation beyond steady state. These results support further investigation of BAY 59-7939 in phase II clinical trials.