title: Direct and rapid inhibition of factor Xa by otamixaban: a pharmacokinetic and pharmacodynamic investigation in patients with coronary artery disease.
abstract: BACKGROUND
  New anticoagulants that combine effective anticoagulation with low bleeding rates are still sought after. We investigated the safety, pharmacokinetics, and pharmacodynamics of otamixaban, a direct factor Xa inhibitor, in patients with stable coronary artery disease.
  
  
  METHODS
  This was a randomized, placebo-controlled, double-blind, multicenter study in 119 patients with stable coronary artery disease taking maintenance doses of their comedication. Of these patients, 50% had mild renal impairment (creatinine clearance >45 mL/min but <80 mL/min). Patients were randomized in a 4:1 ratio to receive either otamixaban or placebo as a 1-minute bolus followed by a 24-hour continuous infusion. Anti-factor Xa activity, clotting times (activated partial thromboplastin time, dilute prothrombin time, Russell's viper venom test), and international normalized ratio were measured.
  
  
  RESULTS
  All patients completed the study according to the protocol. No major or minor bleeding occurred according to Thrombosis in Myocardial Infarction criteria. Anti-factor Xa activity and anticoagulant effect were measurable early after the start of the infusion and remained during the infusion. Upon cessation, these effects declined rapidly and returned to baseline within 6 hours after the end of infusion. Anti-factor Xa activity coincided with the otamixaban plasma concentrations. The fold changes from baseline at the end of infusion with regard to the clotting times ranged from 1.7 to 4.4 (1.15 for placebo), 1.29 to 3.15 (0.98 for placebo), and 1.19 to 2.11 (0.94 for placebo) for Russell's viper venom test, dilute prothrombin time, and activated partial thromboplastin time, respectively, and ranged from 0.94 to 1.70 (0.94 for placebo) for the international normalized ratio.
  
  
  CONCLUSIONS
  In patients with stable coronary artery disease taking maintenance doses of their usual concomitant medication, otamixaban exerts a rapid onset of anticoagulation and anti-factor Xa activity. Our data provide evidence that further studies are warranted to investigate the safety and efficacy of otamixaban in the target population.
authors.affiliation: Science & Medical Affairs, Sanofi-Aventis, Frankfurt am Main, Germany. markus.hinder@sanofi-aventis.com
authors.forename: Markus
authors.initials: M
authors.lastname: Hinder
authors.forename: Annke
authors.initials: A
authors.lastname: Frick
authors.forename: Pierre
authors.initials: P
authors.lastname: Jordaan
authors.forename: Galina
authors.initials: G
authors.lastname: Hesse
authors.forename: Alexander
authors.initials: A
authors.lastname: Gebauer
authors.forename: Jochen
authors.initials: J
authors.lastname: Maas
authors.forename: Anne
authors.initials: A
authors.lastname: Paccaly
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D015897:Comorbidity; D003327:Coronary Disease / Q000188:drug therapy* / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004311:Double-Blind Method; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D019934:International Normalized Ratio; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D003497:Cyclic N-Oxides; D065427:Factor Xa Inhibitors; D011725:Pyridines; C435830:otamixaban