Levetiracetam therapeutic monitoring in patients with epilepsy - Effect of concomitant antiepileptic drugs

The authors assessed the effect of concomitant antiepileptic therapy on steady-state plasma concentrations of the new antiepileptic drug (AED) levetiracetam in a cohort of 100 adult patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two groups, otherwise comparable for age, gender, weight-adjusted daily dose of levetiracetam, and dosing frequency: group A (n = 65), receiving levetiracetam plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin; group B (n=35), receiving levetiracetam plus AEDs without inducing properties of CYP metabolism, namely valproic acid and lamotrigine. Plasma levetiracetam concentrations were measured by HPLC with spectrophotometric detection. Median morning trough levetiracetam plasma concentrations were significantly lower in patients of group A than in patients of group B (10.4 mug/mL versus 4.7 mug/mL, P < 0.001). Median weight-normalized levetiracetam apparent oral clearance (CL/F) was 1.3-fold in patients receiving AED inducers compared with patients on AED non inducers (1.93 versus 1.45 mL (.) min(-1) (.) kg(-1), P < 0.001). No gender-related difference was observed in CL/F values. Levetiracetam plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 500 to 5000 mg/d, although at a given daily dose an appreciable interpatient variability was observed in matched plasma drug concentrations. Concomitant AED inducers can contribute to variability in levetiracetam disposition in patients with epilepsy. The observed differences were moderate and possibly of minor clinical significance.