Levetiracetam, a new antiepileptic agent: Lack of in vitro and in vivo pharmacokinetic interaction with valproic acid

Purpose: The novel antiepileptic drug (AED) levetiracetam (LEV; Keppra) has a wide therapeutic index and pharmacokinetic characteristics predicting limited drug-interaction potential. It is indicated as an add-on treatment in patients with epilepsy, and thus coadministration with valproic acid (VPA) is likely. These studies were performed to determine whether coadministration of LEV with VPA might result in pharmacolcinetic interactions. Methods: In vitro assays were performed to characterize the transformation of LEV into its main in vivo metabolite UCB L057. The reaction was examined for its sensitivity to clinically relevant concentrations of VPA. An open-label, one-way, one-sequence crossover clinical trial was conducted in 16 healthy volunteers to assess further the possibility of any relevant pharmacokinetic interaction. Results: Human whole blood and, to a lesser extent, human liver homogenates were demonstrated to hydrolyze LEV to UCB L057, its main metabolite. The reaction possibly involves type-B esterases and is not affected by 1 mM VPA (i.e., 166 mug/ml). Pharmacokinetic parameters of a single dose of LEV (1,500 mg) coadmistered with steady-state concentrations of VPA (8 days of 500 mg, b.i.d.) did not differ significantly from the pharmacokinetics of LEV administered alone [area under the curve (AUC) of 397 and 400 g/h/ml, respectively]. Furthermore, LEV did not affect the steady-state pharmacokinetics of VPA. Conclusions: These findings suggest the absence of a pharmacokinetic interaction between VPA and LEV during short-term administration, and suggest that dose adjustment is not required when these two drugs are given together.