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 Zafar; David A. Vorchheimer; Juan Gaztanaga; Mauricio Velez; Daniel Yadegar; Pedro R. Moreno; Satoshi Kunitada; Juan Pagan; Valentin Fuster; Juan J. Badimon

doi:10.1160/TH07-04-0312

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(04): 883-888
DOI: 10.1160/TH07-04-0312

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

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

Authors

Mohammad Urooj Zafar

¹Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA
David A. Vorchheimer

¹Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA
Juan Gaztanaga

¹Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA
Mauricio Velez

¹Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA
Daniel Yadegar

¹Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA
Pedro R. Moreno

¹Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA
Satoshi Kunitada

²Daiichi Sankyo Pharma Development, Tokyo, Japan
Juan Pagan

²Daiichi Sankyo Pharma Development, Tokyo, Japan
Valentin Fuster

¹Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA
Juan J. Badimon

¹Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA

Abstract

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.

Keywords

Atherothrombosis - clinical trials - oral anticoagulants - coagulation inhibitors - factor X - thrombosis

Full Text

References

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