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

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.

[1]  V. Fuster,et al.  Antithrombotic Effects of DX-9065a, a Direct Factor Xa Inhibitor , 2002, Thrombosis and Haemostasis.

[2]  A. Rezaie,et al.  Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin-antithrombin complex. , 2001, Blood.

[3]  T. Hastie,et al.  Low-Molecular-Weight Heparins Compared with Unfractionated Heparin for Treatment of Acute Deep Venous Thrombosis , 1999, Annals of Internal Medicine.

[4]  B. Eriksson,et al.  A Once-Daily, Oral, Direct Factor Xa Inhibitor, Rivaroxaban (BAY 59-7939), for Thromboprophylaxis After Total Hip Replacement , 2006, Circulation.

[5]  B. Ibáñez,et al.  A novel anti‐ischemic nitric oxide donor (LA419) reduces thrombogenesis in healthy human subjects , 2007, Journal of thrombosis and haemostasis : JTH.

[6]  J. Badimón,et al.  Antithrombotic Effect of Tissue Factor Inhibition by Inactivated Factor VIIa: An Ex Vivo Human Study , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[7]  V. Fuster,et al.  Potent arterial antithrombotic effect of direct factor-Xa inhibition with ZK-807834 administered to coronary artery disease patients , 2007, Thrombosis and Haemostasis.

[8]  S. Yusuf,et al.  Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. , 2006, JAMA.

[9]  J. Hirsh Drug therapy : heparin , 1991 .

[10]  J. Hirsh,et al.  New antithrombotic agents , 1999, The Lancet.

[11]  V. Fuster,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. , 1999, Circulation.

[12]  B. Eriksson,et al.  Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. , 2001, The New England journal of medicine.

[13]  B. Eriksson,et al.  Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. , 2002, Archives of internal medicine.

[14]  V. Fuster,et al.  Antithrombotic effects of abciximab. , 2000, The American journal of cardiology.

[15]  D. Kubitza,et al.  Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases , 2006, Expert opinion on investigational drugs.

[16]  V. Fuster,et al.  Clinical and Experimental Experience with Factor Xa Inhibitors , 2004, American journal of cardiovascular drugs : drugs, devices, and other interventions.

[17]  J. Badimón,et al.  Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r‐hirudin in a human ex vivo model of arterial thrombosis , 2003, Journal of thrombosis and haemostasis : JTH.

[18]  P. Armstrong,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 , 2005, Journal of thrombosis and haemostasis : JTH.

[19]  K. Furie,et al.  Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. , 2007, Circulation.

[20]  V. Fuster,et al.  Acute Antithrombotic Effect of a Front-Loaded Regimen of Clopidogrel in Patients With Atherosclerosis on Aspirin , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[21]  V. Fuster,et al.  Tissue Factor Coagulation Pathway: A New Therapeutic Target in Atherothrombosis , 2004, Journal of cardiovascular pharmacology.

[22]  J. Eikelboom,et al.  Low-Molecular-Weight Heparin Compared with Intravenous Unfractionated Heparin for Treatment of Pulmonary Embolism , 2004, Annals of Internal Medicine.

[23]  A. Frick,et al.  Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, and acetylsalicylic acid , 2006, Thrombosis and Haemostasis.

[24]  Zahi A Fayad,et al.  Atherothrombosis and high-risk plaque: part I: evolving concepts. , 2005, Journal of the American College of Cardiology.