Prospective assessment of levetiracetam pharmacokinetics during dose escalation in 4-to 12-year-old children with partial-onset seizures on concomitant carbamazepine or valproate

Purpose: To assess the multiple-dose pharmacokinetics of levetiracetam and its major metabolite ucb L057 in children with partial-onset seizures and determine whether it is affected by adjunctive carbamazepine or valproate. To correlate levetiracetam concentrations in plasma and saliva and to assess its safety and clinical response. Methods: Design was an open-label, multicenter study. Twenty-one children (4-12 years old) with epilepsy taking carbamazepine (13) or valproate (8) received adjunctive levetiracetam. Levetiracetam was initiated at 20mg/(kg day) and titrated at 2-week intervals to 40 and then 60mg/(kg day). Twelve-hour pharmacokinetics were determined at the end of each 2-week period. Efficacy was estimated from the partial seizure frequency per week and Global Evaluation Scale. Results: Levetiracetam was rapidly absorbed following oral dosing, with median t(max) of 0.5 h. Dose proportional increases were observed for C-max and AUC((0-1 2)) over the dose range; t(1/2) was 4.9 h. Pharmacokinetics of levetiracetam and ucb L057 were not markedly different with concomitant carbamazepine or valproate; clearance was only 7-13% faster and AUC was decreased by only 15-24% in those on carbamazepine compared to valproate. Levetiracetam did not affect trough carbamazepine or valproate. Concentration in saliva and plasma were strongly correlated. Seizure frequency declined by 50% or more in 43% of subjects in the intent-to-treat population (n = 21) and in 56% of those with seizures at baseline (n = 16). Marked or moderate improvement occurred in 80% and 75% of patients based on Global Evaluation Scale ratings by investigators and parents/guardians, respectively. Levetiracetam was well tolerated. Conclusion: Levetiracetam exhibits simple pharmacokinetics in children, with rapid absorption and dose-proportional kinetics. Small but not clinically relevant differences were observed between subjects receiving carbamazepine and valproate, suggesting significant dose adjustment is usually not necessary. This substantiates prior assessments that levetiracetam clearance is higher in children than adults, necessitating a higher dose in children on a mg/kg basis, and suggests it is useful add-on therapy for children with partial-onset seizures regardless of baseline therapy. (c) 2007 Elsevier B.V. All rights reserved.