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Pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban: a randomized study in healthy subjects
Author(s) -
Kubitza Dagmar,
Becka Michael,
Mück Wolfgang,
Krätzschmar Jöern
Publication year - 2014
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12349
Subject(s) - pharmacodynamics , pharmacokinetics , rivaroxaban , warfarin , pharmacology , medicine , randomized controlled trial , atrial fibrillation
Aims 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 X a activity, inhibition of factor X a 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 X a 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 X a 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 X a activity.