title: Pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban: a randomized study in healthy subjects.
abstract: OBJECTIVE
  This study investigated relevant pharmacodynamic and pharmacokinetic parameters during the transition from warfarin to rivaroxaban in healthy male subjects.
  
  
  METHODS
  Ninety-six healthy men were randomized into the following three groups: warfarin [international normalized ratio (INR) 2.0-3.0] transitioned to rivaroxaban 20 mg once daily (od; group A); warfarin (INR 2.0-3.0) followed by placebo od (group B); and rivaroxaban alone 20 mg od (group C) for 4 days. Anti-factor Xa activity, inhibition of factor Xa activity, prothrombin time (PT), activated partial thromboplastin time, HepTest, prothrombinase-induced clotting time, factor VIIa activity, factor IIa activity, endogenous thrombin potential and pharmacokinetics were measured.
  
  
  RESULTS
  An additive effect was observed on the PT and PT/INR during the initial transition period. The mean maximal prolongation of PT was 4.39-fold [coefficient of variation (CV) 18.03%; range 3.39-6.50] of the baseline value in group A, compared with 1.88-fold (CV 10.35%; range 1.53-2.21) in group B and 1.57-fold (CV 9.98%; range 1.37-2.09) in group C. Rivaroxaban had minimal influence on the PT/INR at trough levels. Inhibition of factor Xa activity, activated partial thromboplastin time and endogenous thrombin potential were also enhanced, but to a lesser extent. In contrast, the effects of rivaroxaban on anti-factor Xa activity, HepTest and prothrombinase-induced clotting time were not affected by pretreatment with warfarin.
  
  
  CONCLUSIONS
  Changes in pharmacodynamics during the transition from warfarin to rivaroxaban vary depending on the test used. A supra-additive effect on PT/INR is expected during the initial period of transition, but pretreatment with warfarin does not influence the effect of rivaroxaban on anti-factor Xa activity.
authors: Clinical Sciences, Bayer HealthCare, Wuppertal, Germany.
authors: Dagmar
authors: D
authors: Kubitza
authors: Michael
authors: M
authors: Becka
authors: Wolfgang
authors: W
authors: Mück
authors: Jöern
authors: J
authors: Krätzschmar
mesh_terms: D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000493:pharmacokinetics / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D015942:Factor VIIa / Q000032:analysis; D015951:Factor Xa / Q000032:analysis; D064368:Healthy Volunteers; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000493:pharmacokinetics / Q000494:pharmacology; D011516:Prothrombin / Q000032:analysis; D011517:Prothrombin Time; D000069552:Rivaroxaban; D013876:Thiophenes / Q000493:pharmacokinetics / Q000494:pharmacology; D014859:Warfarin / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D009025:Morpholines; D013876:Thiophenes; D014859:Warfarin; D011516:Prothrombin; C025337:Factor IIa; D000069552:Rivaroxaban; D015942:Factor VIIa; D015951:Factor Xa
keywords: international normalized ratio; pharmacodynamics; prothrombin time; rivaroxaban; therapy transition; warfarin