Switching from rivaroxaban to warfarin: an open label pharmacodynamic study in healthy subjects

Abstract

Aims: The primary objective was to explore the pharmacodynamic changes during transition from rivaroxaban to warfarin in healthy subjects. Safety, tolerability and pharmacokinetics were assessed as secondary objectives.

Methods: An open label, non-randomized, sequential two period study. In treatment period 1 (TP1), subjects received rivaroxaban 20 mg once daily (5 days), followed by co-administration with a warfarin loading dose regimen of 5 or 10 mg (for the 10 mg regimen, the dose could be uptitrated to attain target international normalized ratio [INR] ≥2.0) once daily (2-4 days). When trough INR values ≥2.0 were attained, rivaroxaban was discontinued and warfarin treatment continued as monotherapy (INR 2.0-3.0). During treatment period 2, subjects received the same warfarin regimen as in TP1, but without rivaroxaban.

Results: During co-administration, maximum INR and prothrombin time (PT) values were higher than with rivaroxaban or warfarin monotherapy. The mean maximum effect (Emax ) for INR after co-administration was 2.79-4.15 (mean PT Emax 41.0-62.7 s), compared with 1.41-1.74 (mean PT Emax 20.1-25.2 s) for warfarin alone. However, rivaroxaban had the smallest effect on INR at trough rivaroxaban concentrations. Neither rivaroxaban nor warfarin significantly affected maximum plasma concentrations of the other drug.

Conclusions: The combined pharmacodynamic effects during co-administration of rivaroxaban and warfarin were greater than additive, but the pharmacokinetics of both drugs were unaffected. Co-administration was well tolerated. When transitioning from rivaroxaban to warfarin, INR monitoring during co-administration should be performed at the trough rivaroxaban concentration to minimize the effect of rivaroxaban on INR.

Trial registration: ClinicalTrials.gov NCT01400646.

Keywords: pharmacodynamic; pharmacokinetic; rivaroxaban; switching; warfarin.

© 2014 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

Figures

Figure 1

Study design. *Initially, subjects received warfarin 5 mg once daily during the first treatment period but because only a small proportion of subjects reached the trough INR ≥2.0 within the time frame allowed by the study (maximum of 4 days), the protocol was amended to allow all subsequent subjects to receive warfarin 10 mg once daily instead. INR, international normalized ratio

Figure 2

Mean (SD) international normalized ratio–time profile with (A) 5 mg and (B) 10 mg warfarin loading dose regimens during both treatment periods for subjects who completed both periods. Days 7.1 and 7.2 are repeats of day 7 sampling for subjects requiring additional days of rivaroxaban and warfarin co-administration to reach the required INR (part of the maximum 4 day co-administration phase) during TP1. Days 2.1 and 2.2 are the corresponding days during TP2. These are equivalent to days 7.1 and 7.2 TP1 but without the 5 day lead-in period of rivaroxaban dosing. INR, international normalized ratio; SD, standard deviation; TP1, treatment period 1; TP2, treatment period 2. , TP1; , TP2