Lack of effect of repeated administration of levetiracetam on the pharmacodynamic and pharmacokinetic profiles of warfarin

Abstract

The objective of this study was to determine if repeated administration of levetiracetam alters the pharmacokinetics or the pharmacodynamics of warfarin. Forty-two healthy subjects (18–50 years old) were recruited into the study. After a dose-finding phase and a stabilization phase, during which a warfarin treatment was introduced and the dose maintained stable for at least 5 days, 18 male and 8 female subjects were eligible and enrolled. Subjects received warfarin (2.5, 5 or 7.5 mg/day) plus levetiracetam 1000 mg bid, and warfarin plus placebo. The treatment periods were 7 days long and were separated by a 3-day wash-out period. The protein binding and the pharmacokinetic profiles of R- and S-warfarin were assessed at steady state by analysis of blood samples, and the anticoagulant effect was measured using the international normalized ratio (INR). The ratios of the geometric means for AUC ss (90% confidence interval) between coadministration of warfarin with levetiracetam or with placebo were 97.17% (92.85%, 101.68%) for R-warfarin and 100.16% (96.43%, 104.02%) for S-warfarin. Results for C max, C min and oral clearance were consistent with those of AUC ss. In addition, the protein binding of warfarin was not affected by the concomitant treatment. The INR values measured the last 5 days of each period were not statistically altered by the concomitant administration of levetiracetam or placebo: 1.59±0.18 for warfarin alone, 1.49±0.21 when coadministered with placebo, and 1.55±0.23 with levetiracetam (means±S.D.). The frequency and profile of adverse events under the concomitant therapy of warfarin and levetiracetam were expected for subjects receiving these drugs, and the coadministration was safe. Moreover, levetiracetam pharmacokinetics after repeated warfarin administration did not differ from those previously reported in healthy volunteers. At the doses administered, there is no evidence of a pharmacokinetic or pharmacodynamic interaction between warfarin and levetiracetam.