Population Pharmacokinetics of Valproate in Children: The Importance of Total Daily Dose, Compliance and Co-Treatment

Abstract Valproate represents one of the most commonly used anticonvulsants worldwide, whose narrow therapeutic range and high potential for drug-drug interactions leads to pronounced intra- and inter-individual variability in plasma concentration and response. The aim of our study was to apply population pharmacokinetics analysis to comprehensively investigate and detect the most important factors affecting pharmacokinetics of valproate in Serbian children with epilepsy. This retrospective observational study was based on demographic and medical data retrieved from the medical records on epileptic patients treated with valproate at the pediatric department of the Clinical Centre, Kragujevac, Serbia. Valproate serum concentrations were obtained as a part of routine medical practice. Population pharmacokinetics analysis was performed by MonolixSuite 2019R1 (Lixoft, Antony, France) software, using one-compartment model with first order absorption and linear elimination. The study included 1642 valproate concentrations obtained from 232 patients, of which 201 (1420 concentrations) were included in the index set used for the modelling, while the other 31 (222 concentrations) were the validation set used for external validation of the final model. Covariate testing based on the whole index set revealed that only total daily valproate dose significanly affected the clearance of valproate: Cl (l/h)= 0.135×1.002 DD . When only compliant patients were included, co-treatment with carbamazepine was shown to be of significance as well: Cl(l/h)=0.121×1.002 DD ×1.2 CBZ . Our study demonstrated that valproate clearance correlates with total valproate daily dose. The influence of co-treatment with carbamazepine on valproate pharmacokinetics can be observed and used for clearance estimation only in compliant patients.