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

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

• References

• 1 Rosamond W, Flegal K, Friday G. et al. Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.. Circulation 2007; 115: e69-171.
• 2 Hirsh J. Heparin.. N Engl J Med 1991; 324: 1565-1574.
• 3 Hirsh J, Weitz JI. New antithrombotic agents.. Lancet 1999; 353: 1431-1436.
• 4 Rezaie AR. Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin- antithrombin complex.. Blood 2001; 97: 2308-2313.
• 5 Gould MK, Dembitzer AD, Doyle RL. et al. Lowmolecular- weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials.. Ann Intern Med 1999; 130: 800-809.
• 6 Quinlan DJ, McQuillan A, Eikelboom JW. Lowmolecular- weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials.. Ann Intern Med 2004; 140: 175-183.
• 7 Eriksson BI, Bauer KA, Lassen MR. et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery.. N Engl J Med 2001; 345: 1298-1304.
• 8 Turpie AG, Bauer KA, Eriksson BI. et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies.. Arch Intern Med 2002; 162: 1833-1840.
• 9 Kubitza D, Haas S. Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases.. Expert Opin Investig Drugs 2006; 15: 843-855.
• 10 Agnelli G, Becattini C. New anticoagulants.. Semin Thromb Hemost 2006; 32: 793-802.
• 11 Eriksson BI, Borris LC, Dahl OE. et al. A oncedaily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59–7939), for thromboprophylaxis after total hip replacement.. Circulation 2006; 114: 2374-2381.
• 12 Alexander JH, Yang H, Becker RC. et al. First experience with direct, selective factor Xa inhibition in patients with non-ST-elevation acute coronary syndromes: results of the XaNADU-ACS Trial.. J Thromb Haemost 2005; 3: 439-447.
• 13 Zafar MU, Farkouh ME, Osende J. et al. Potent arterial antithrombotic effect of direct factor-Xa inhibition with ZK-807834 administered to coronary artery disease patients.. Thromb Haemost 2007; 97: 487-492.
• 14 Hinder M, Frick A, Rosenburg R. et al. Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, and acetylsalicylic acid.. Thromb Haemost 2006; 95: 224-228.
• 15 Sarich TC, Osende JI, Eriksson UG. et al. Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis.. J Thromb Haemost 2003; 1: 999-1004.
• 16 Lev EI, Marmur JD, Zdravkovic M. et al. Antithrombotic effect of tissue factor inhibition by inactivated factor VIIa: an ex vivo human study.. Arterioscler Thromb Vasc Biol 2002; 22: 1036-1041.
• 17 Zafar MU, Vilahur G, Choi BG. et al. A novel antiischemic nitric oxide donor (LA419) reduces thrombogenesis in healthy human subjects.. J Thromb Haemost 2007; 5: 1195-1200.
• 18 Fuster V, Moreno PR, Fayad ZA. et al. Atherothrombosis and high-risk plaque: part I: evolving concepts.. J Am Coll Cardiol 2005; 46: 937-954.
• 19 Viles-Gonzalez JF, Anand SX, Zafar MU. et al. Tissue factor coagulation pathway: a new therapeutic target in atherothrombosis.. J Cardiovasc Pharmacol 2004; 43: 669-676.
• 20 Badimon JJ, Lettino M, Toschi V. et al. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions.. Circulation 1999; 99: 1780-1787.
• 21 Viles-Gonzalez JF, Gaztanaga J, Zafar MU. et al. Clinical and experimental experience with factor Xa inhibitors.. Am J Cardiovasc Drugs 2004; 4: 379-384.
• 22 Hirsh J. New anticoagulants.. Am Heart J 2001; 142 (Suppl. 02) S3-8.
• 23 Yusuf S, Mehta SR, Chrolavicius S. et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial.. J Am Med Assoc 2006; 295: 1519-1530.
• 24 Hayes R, Chesebro JH, Fuster V. et al. Antithrombotic effects of abciximab.. Am J Cardiol 2000; 85: 1167-1172.
• 25 Shimbo D, Osende J, Chen J. et al. Antithrombotic effects of DX-9065a, a direct factor Xa inhibitor: a comparative study in humans versus low molecular weight heparin.. Thromb Haemost 2002; 88: 733-738.
• 26 Helft G, Osende JI, Worthley SG. et al. Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin.. Arterioscler Thromb Vasc Biol 2000; 20: 2316-2321.