A Review of Population Pharmacokinetic Studies of Levetiracetam

BackgroundLevetiracetam 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. ObjectiveThe aim of this review was to provide a synopsis for population pharmacokinetic studies of levetiracetam and explore the identified influencing covariates. MethodsWe systematically searched the PubMed and Embase databases from inception to 30 June, 2020. The information on study designs, target population, model characteristics, and identified covariates was summarised. Moreover, the pharmacokinetic profiles were compared among neonates, children, and adults. ResultsFourteen studies were included, among which 2 involved neonates, 4 involved children, 2 involved both children and adults, and 6 involved only adults. The median value of apparent clearance for children (0.074 [range: 0.038-0.079] L/h/kg) was higher than that for adults (0.054 [range: 0.039-0.061] L/h/kg). Body weight was found to significantly 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%-22%, whereas co-administration with valproate acid decreased it by 18.8%. ConclusionLevetiracetam 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. Key pointsO_LIThis review identifies weight, renal function, daily dose, and postmenstrual age as the covariates that most likely influence the levetiracetam (LEV) pharmacokinetics. C_LIO_LIChildren showed higher clearance per kilogram body weight than adults, indicating that a higher dosage is required for children per kilogram body weight. C_LIO_LIFurther PPK studies are needed to evaluate LEV pharmacokinetics in special populations such as pregnant women and neonates. C_LI