Population Pharmacokinetics of??Levetiracetam in Japanese and??Western Adults

Abstract

To assess the population pharmacokinetics of levetiracetam, a second-generation antiepileptic drug, in adult Japanese and Western populations. Data were pooled from ten matched clinical trials conducted in Japan and in Europe and the USA, in which levetiracetam was administered orally to healthy subjects and subjects with epilepsy. Overall, 5408 plasma concentrations were available from 524 subjects in six clinical pharmacology studies and two confirmatory and two long-term safety studies of add-on treatment for partial epilepsy. A one-compartment open model with first-order absorption and elimination was fitted to the plasma concentrations using nonlinear mixed-effects modelling with first-order estimation. Ethnicity had no statistically significant effect on the pharmacokinetics of levetiracetam in the presence of the other covariates. Bodyweight, sex, creatinine clearance and concomitant intake of enzyme inducers or valproic acid had a statistically significant effect on apparent plasma clearance of levetiracetam. Bodyweight, disease and valproic acid had a statistically significant effect on the volume of distribution. Levetiracetam exposure (the area under the plasma concentration-time curve over the 12-hour dosing interval at steady state) was 12% higher in females than in males. Decreasing bodyweight from 70 kg to 40 kg was predicted to increase exposure by 16%, while halving creatinine clearance was predicted to increase exposure by 10%. Enzyme inducers reduced exposure by 8%, while valproic acid resulted in a 23% increase in exposure. The latter effect was assumed to arise from the known association between valproic acid and increased body fat, since levetiracetam is negligibly metabolised by cytochrome P450 enzymes. Population pharmacokinetic analysis points to the absence of ethnic differences in the pharmacokinetics of levetiracetam between Japanese and Western populations, other than those arising from bodyweight differences. Small, clinically non-relevant differences between individual demographic characteristics suggest that dose adjustment is usually not necessary.