Population Pharmacokinetics Model and Simulation of Unbound and Total Valproic Acid in Epileptic Children Using a Protein Binding Model

Valproic acid (VPA), a classic antiepileptic drug with a narrow therapeutic window, is widely used in paediatric epilepsy treatment. As only the unbound fraction of the drug is a pharmacologically active component, we established a population pharmacokinetic (PopPK) model for both unbound and total VPA in epileptic children to provide a clinical optimisation strategy. A total of 450 epileptic children providing 620 samples were included for modelling development. In addition, trough unbound and total VPA concentrations were simulated for typical patients to propose the dose regimen. A one-compartment model with first-order absorption and elimination was well developed to describe the pharmacokinetic characteristics of unbound VPA, and the Langmuir equation was used to explore the protein binding parameters. The final model indicated that the CL_u/F of unbound VPA was significantly influenced by body weight, age-based maturation and daily dose. Proposed dosing regimens for children aged 0 to 12 years, simulated using the Monte Carlo method, recommended 10-30 mg/kg/day, decreasing with age. This PopPK model of VPA could be helpful to propose recommended dosage regimens to achieve the target therapeutic concentration window in clinical practice.