Direct and specific inhibition of
factor Xa is an emerging therapeutic strategy for atherothrombotic disease. Parenteral
factor Xa inhibitors promise efficacy comparable to standard
therapies, which could be extended to ambulatory patients with oral agents. We evaluated the antithrombotic effect of the oral,
direct factor Xa inhibitor DU-176b in a phase-I study. Healthy subjects (n = 12) received a single, 60 mg dose of
DU-176b. Antithrombotic effects were assessed by comparing ex-vivo
thrombus formation at 1.5, 5, and 12 hours post-dose versus baseline, along with
factor Xa activity,
thrombin generation and clotting parameters. Under venous flow after 1.5 and 5 hours, the
thrombus was 28% and 21% smaller versus baseline, respectively (p < 0.05). Under arterial condition, the reduction was 26% and 17% (p < 0.05).
Thrombin generation decreased by 28% at 1.5 hours and 10% at 5 hours. Changes in PT and INR correlated well with plasma
drug concentrations (R2 = 0.79 and 0.78). Direct and specific inhibition of
factor Xa by
DU-176b significantly reduced ex-vivo
thrombus formation at both venous and arterial rheologies, up to 5 hours post-dose. The effects mirrored changes in clotting parameters, suggesting their potential usefulness for monitoring in a clinical setting.