Effect of levetiracetam on the pharmacokinetics of adjunctive antiepileptic drugs: A pooled analysis of data from randomized clinical trials

The purpose of this study was to determine the influence of levetiracetam on the steady-state serum concentrations of other commonly used antiepileptic drugs (AEDs). Serum AED concentrations were measured at baseline and after adjunctive therapy with levetiracetam (1000-4000 mg/day) or placebo in four phase III trials in patients with refractory partial epilepsy receiving stable AED dosages. The data were pooled, and repeated measures covariance analysis was used to calculate the ratio (and 90% confidence intervals) of the geometric mean serum drug concentrations during adjunctive levetiracetam therapy relative to baseline. Levetiracetam did not increase or decrease mean steady-state serum concentrations of carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. For each of these AEDs, the 90% confidence interval of the geometric mean drug concentrations ratio was included within the 80-125% bioequivalence range. Serum concentrations of these AEDs did not change over time after adjunctive levetiracetam therapy, irrespective of the dosage of levetiracetam used. For vigabatrin, there was no evidence for a significant change in serum drug concentration after the addition of levetiracetam, but the number of observations was too small for the limits of the confidence interval to fall within the 80-125% range. Thus, adjunctive therapy with levetiracetam does not influence the steady-state serum concentrations of concomitantly administered carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. Consequently, no need for adjusting the dosages of these AEDs is anticipated when levetiracetam is added on or removed from a patient's therapeutic regimen.