Effect of Carisbamate on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Participants

Abstract

Carisbamate's effect (200 mg twice-daily [study 1], 600 mg twice-daily [study 2]) on warfarin's (25 mg single dose) pharmacokinetics and pharmacodynamics (international normalized ratio) was assessed during 2 open-label studies in healthy participants. Coadministration of either carisbamate regimen produced small changes on the mean maximum plasma concentration (C(max)) and mean area under the plasma concentration-time curve to the last measurable time point (AUC(last)) of (S)- and (R)-warfarin, which are unlikely to be clinically significant. For (S)-warfarin, the ratios (with carisbamate/without carisbamate) of geometric means for C(max) were 105.44 (study 1) and 98.48 (study 2) and for AUC(last) were 109.33 (study 1) and 114.43 (study 2); the corresponding 90% confidence intervals were within the bioequivalence limits of 80% to 125%. Results were similar for (R)-warfarin. Carisbamate at 600 mg (but not 200 mg) twice-daily prolonged the elimination half-life of (S)- and (R)-warfarin by ~10 hours (25% and 32% increase, respectively). Prothrombin time was unaltered by either carisbamate dose. Adverse events with the highest incidence were dizziness (50%) and headache (50%) in study 1 and somnolence (56%) in study 2. Warfarin exposure and international normalized ratio were unaffected by coadministration of carisbamate 200 mg or 600 mg twice-daily. Carisbamate was well tolerated.