A Review of Population Pharmacokinetic Studies of Levetiracetam

Background: Levetiracetam has been widely used as a treatment option for different types of epilepsy in both adults and children. Because of its large between-subject variability, several population pharmacokinetic studies have been performed to identify its pharmacokinetic covariates, and thus facilitate individualised therapy. Objective: The aim of this review was to provide a synopsis for population pharmacokinetic studies of levetiracetam and explore identified influencing covariates. Methods: We systematically searched PubMed and Embase databases from inception to June 30, 2020. The information on study designs, target population, model characteristics, and identified covariates were summarised. Moreover, the pharmacokinetic profiles were compared among neonates, children, and adults. Results: A total of 14 studies were included, among which two involved neonates, four involved children, two involved both children and adults, and six involved only adults. The median value of apparent clearance for children (0.074 [range: 0.038 to 0.079] L/h/kg) was higher than that for adults (0.054 [range: 0.039 to 0.061] L/h/kg). Body weight was found to influence the apparent clearance and volume of distribution significantly, whereas renal function influenced the clearance. Likewise, co-administration with enzyme-inducing antiepileptic drugs (such as carbamazepine and phenytoin) increased the drug clearance by 9 to 22%, whereas coadministration with valproate acid decreased it by 18.8%. Conclusion: Levetiracetam dose regimen is dependent on the body size and renal function of patients. Further studies are needed to evaluate levetiracetam pharmacokinetics in neonates and pregnant women.