Factors influencing valproate pharmacokinetics in children and adults.

OBJECTIVE The aim of the present study was to build population pharmacokinetic models for the clearance of valproate (VPA) in 2 separate populations of Serbian patients with epilepsy, children and adults. METHODS Analysis was performed using 65 and 63 steady-state concentrations of VPA collected from 58 children and 60 adult epileptic patients, respectively. Mean values for total body weight and age were 27.07 ± 13.08 kg and 7.21 ± 3.63 years in the pediatric population, and 69.67 ± 15.60 kg and 33.97 ± 16.41 years in the adult population. The one-compartment model with first order elimination and without absorption was used from the PREDPP (Prediction for Observation Population Pharmacokinetics) library of NONMEM software. RESULTS The derived final models show that VPA clearance increased with total body weight of patients in both populations. However, the carbamazepine comedication was the main determinant of the final model in children whereas phenobarbitone comedication was the most important factor in the adult population. The magnitudes of these effects were +0.159 lh-1 and +0.539 lh-1 for carbamazepine and phenobarbitone, respectively. A significant decrease in interindividual and intraindividual variability was observed in the target populations. The pharmacokinetic models obtained were validated in groups of 15 epileptic patients, each showing good predictive performance of the model. CONCLUSIONS The derived models describe well VPA clearance in terms of characteristics of Serbian pediatric and adult epileptic patients, offering a basis for rational individualization of VPA dosage regimens.