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

The objective of this study was to determine if repeated administration of levetiracetam alters the pharmacokinetics or the pharmacodynamics of warfar in. Forty-two healthy subjects (18-50 years old) were recruited into the st udy. After a dose-finding phase and a stabilization phase, during which a w arfarin treatment was introduced and the dose maintained stable for at leas t 5 days, 18 male and 8 female subjects were eligible and enrolled. Subject s 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 pharmacok inetic profiles of R- and S-warfarin were assessed at steady state by analy sis of blood samples, and the anticoagulant effect was measured using the i nternational normalized ratio (INR). The ratios of the geometric means for AUC(ss) (90%, confidence interval) between coadministration of warfarin wit h levetiracetam or with placebo were 97.17% (92.85%, 101.68%) for R-warfari n and 100.16% (96.43%, 104.02%) for S-warfarin. Results for C-max, C-min an d oral clearance were consistent with those of AUC(ss). In addition, the pr otein binding of warfarin was not affected by the concomitant treatment. Th e INR values measured the last 5 days of each period were not statistically altered by the concomitant administration of levetiracetam or placebo: 1.5 9 +/- 0.18 for warfarin alone. 1.49 +/- 0.21 when coadministered with place bo, and 1.55 +/- 0.23 with levetiracetam (means +/- S.D.). The frequency an d profile of adverse events under the concomitant therapy of warfarin and l evetiracetam were expected for subjects receiving these drugs, and the coad ministration was safe. Moreover, levetiracetam pharmacokinetics after repea ted warfarin administration did not differ from those previously reported i n healthy volunteers. At the doses administered, there is no evidence of a pharmacokinetic or pharmacodynamic interaction between warfarin and levetir acetam. (C) 2001 Elsevier Science B.V. All rights reserved.