title: 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.
abstract: 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.
authors.affiliation: Cardiovascular Biology Research Lab, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA.
authors.forename: Mohammad Urooj
authors.initials: MU
authors.lastname: Zafar
authors.forename: David A
authors.initials: DA
authors.lastname: Vorchheimer
authors.forename: Juan
authors.initials: J
authors.lastname: Gaztanaga
authors.forename: Mauricio
authors.initials: M
authors.lastname: Velez
authors.forename: Daniel
authors.initials: D
authors.lastname: Yadegar
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Moreno
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kunitada
authors.forename: Juan
authors.initials: J
authors.lastname: Pagan
authors.forename: Valentin
authors.initials: V
authors.lastname: Fuster
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Badimon
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000627:therapeutic use*; D000990:Antithrombin III / Q000737:chemistry / Q000494:pharmacology*; D001777:Blood Coagulation; D015951:Factor Xa / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D011517:Prothrombin Time; D013314:Stress, Mechanical; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D013997:Time Factors
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D000990:Antithrombin III; D013917:Thrombin; D015951:Factor Xa