Development of an integrated population pharmacokinetic model for oral levetiracetam in populations of various ages and ethnicities.

Levetiracetam [E Keppra(®)] is a second generation antiepileptic drug for different types of epilepsy in adults and children ≥1 month. The objective is to develop a population pharmacokinetic model to describe the pharmacokinetics of levetiracetam in Japanese children and adults as well as North American children, the purpose being to explore potential dosing recommendations in Japanese children. Levetiracetam plasma concentration-time data were obtained from Japanese adult and pediatric clinical studies. The data were analyzed through non-linear mixed effects modelling. The model was used to perform simulations and compare the exposure in Japanese children and adults. It was subsequently extended to North American children through an external validation. A one-compartment model with first-order absorption and first-order elimination adequately described the data. The exposure parameters determined based on the simulations in children were well within the adult range. The external validation against historical data from North American children was successful. The integrated population pharmacokinetic model provided a good description of the data, confirming the similarity of levetiracetam pharmacokinetics in these various populations. In Japanese children, a target dose of 10 to 30 mg/kg twice daily ensures the same exposure as the recommended dose in Japanese adults of 500 to 1,500 mg twice daily.