A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy

Abstract

The objective of this work was to develop a population pharmacokinetic model for a prolonged-release granule formulation of valproic acid (VPA) in children with epilepsy and to determine the doses providing a VPA trough concentration (Ctrough) within the target range (50-100mg/L). Ninety-eight children (1-17.6years, 325 plasma samples) were included in the study. The model was built with NONMEM 7.3. The probability to obtain Ctrough between 50 and 100mg/L was determined by the Monte Carlo simulations for doses of 20, 30, 40, and 60mg/kg/day and body weights between 10 and 70kg. A one compartment model, with first-order absorption and flip-flop parameterization and linear elimination, but taking protein binding into account, was used to describe the data. Typical values for unbound VPA clearance and distribution volume were 6.24L/h/70kg and 130L/h/70kg respectively. Both parameters were related to body weight via allometric models. The highest probability to obtain a Ctrough within the target range for 10-kg children was obtained with a 40mg/kg daily dose, whereas daily doses of 30 and 20mg/kg were found appropriate for 20 to 30- and ≥ 40-kg children respectively. However, for these same doses, the exposure to unbound VPA could differ by 40%. If the present study supports the current dose recommendations of 20-30mg/kg/day, except for children under 20kg, who may need higher doses, it also highlights the need for further research on the pharmacokinetics/pharmacodynamic profile of unbound VPA.