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

Abstract

AimsThe 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.MethodsAn 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.ResultsDuring 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.ConclusionsThe 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.

Biomarkers for severe eosinophilic asthma

“…For example, the effect of anticoagulation treatments (eg, warfarin) for thromboembolic disease can be assessed by measuring prothrombin time as a pharmacodynamic biomarker. 24 A predictive biomarker identifies patients likely to derive benefit from treatment or identify patients who are unlikely to respond, which thus influences clinical decisions. Although there are no predictive biomarkers for heart failure currently in routine use, 25 predictive biomarkers are used routinely in oncology.…”

Drug-Drug Interactions Leading to Adverse Drug Reactions with Rivaroxaban: A Systematic Review of the Literature and Analysis of VigiBase

“…No clinically relevant PK interactions were observed between rivaroxaban and enoxaparin [ 48 ] or warfarin in phase I studies [ 49 , 50 ]. However, some rivaroxaban PD parameters were affected, and the anti-factor Xa activity of rivaroxaban increased by 50% when coadministered with enoxaparin [ 48 ].…”

Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients

“…Unlike warfarin, which has a significant lag-time to exert PD effects, the anticoagulant activity of FXa inhibitors fluctuates immediately because of changes in plasma drug concentrations. [28][29][30][31] To take into account this characteristic, we modeled the dynamic relationship between PT and probabilities of events, assuming that event risks of FXa inhibitors fluctuated time dependently in accordance with the change in PT. In this model, the predicted event risks may differ between once-daily and twice-daily regimens for the same daily dose.…”

“…We assumed that event risks after administration of FXa inhibitors varied dynamically along with the time-dependent change in PT, because there was a large fluctuation in the PT in patients receiving FXa inhibitors compared with those receiving warfarin. [28][29][30][31] The dynamic relationships between PT ratio and probabilities of ischemic stroke/SE (P ISSE ) and major bleeding (P MB ) were modeled using several functions, and the following functions were adopted in the final model:…”