I. Ragueneau-majlessi et al., Lack of effect of repeated administration of levetiracetam on the pharmacodynamic and pharmacokinetic profiles of warfarin, EPILEPSY R, 47(1-2), 2001, pp. 55-63
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.