Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor

Background and Objective There is a clinical need for new oral anticoagulants to prevent and treat thromboembolic diseases. Given its integral role in the coagulation cascade, factor Xa is a particularly promising target for new anticoagulation therapies. The aim of this study was to investigate the safety, pharmacodynamics, and pharmacokinetics of BAY 59–7939, an oral, direct factor Xa inhibitor. Methods This single–center, randomized, single–blinded, placebo–controlled, dose–escalation study included 108 healthy white male subjects aged 19 to 45 years. Subjects received single oral doses of either BAY 59–7939 (1.25–80 mg) or placebo; in addition, 1 group received 2 doses of BAY 59–7939 (5–mg tablet and oral solution) or placebo in a crossover design. Results Oral BAY 59–7939 in single doses up to 80 mg was safe and well tolerated and was not associated with an increased risk of bleeding compared with placebo. Pharmacodynamic effects (inhibition of factor Xa activity, prothrombin time, activated partial thromboplastin time, and HepTest) and plasma concentration profiles were dose–dependent. Maximum inhibition of factor Xa activity was achieved 1 to 4 hours after administration of BAY 59–7939 and ranged from 20% to 61% for the 5– to 80–mg doses. BAY 59–7939 selectively inhibited factor Xa activity; thrombin (factor IIa) and antithrombin were unaffected. Inhibition of factor Xa activity and prolongation of prothrombin time correlated well with BAY 59–7939 plasma concentrations (r = 0.949 and 0.935, respectively). Conclusions BAY 59–7939 was well tolerated with predictable pharmacodynamics and pharmacokinetics across a wide range of doses in healthy male subjects. BAY 59–7939 was shown to be an effective and specific factor Xa inhibitor. Clinical Pharmacology & Therapeutics (2005) 78, 412–421; doi: 10.1016/j.clpt.2005.06.011