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Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: http://dx.doi.org/10.1160/TH07-04-0312
Issue: 2007: 98/4 (Oct) pp. 705-915
Pages: 883-888

Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber

Mohammad Urooj Zafar1, David A. Vorchheimer1, Juan Gaztanaga1, Mauricio Velez1, Daniel Yadegar1, Pedro R. Moreno1, Satoshi Kunitada2, Juan Pagan2, Valentin Fuster1, Juan J. Badimon1
1Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA; 2Daiichi Sankyo Pharma Development, Tokyo, Japan

Keywords

Clinical trials, thrombosis, oral anticoagulants, factor X, atherothrombosis, coagulation inhibitors

Summary

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.

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