Population Pharmacokinetics of Valproic Acid in Pediatric Patients With Epilepsy: Considerations for Dosing Spinal Muscular Atrophy Patients

摘要

Valproic acid (VPA) dosing strategies used in recent clinical trials in patients with spinal muscular atrophy (SMA) have utilized a paradigm of monitoring trough levels to estimate drug exposure with subsequent dose titration. The validity of this approach remains uncertain and could be improved by understanding sources of pharmacokinetic variability. A population pharmacokinetic analysis of VPA in pediatric patients with epilepsy was recently performed. The pooled data set included 52 subjects with epilepsy, ages 1 to 17 years, who received intravenous and/or various oral formulations. The data was best fit by a 2-compartment model; inclusion of age and weight reduced intersubject variability for clearance (41%), central volume (70%), and peripheral volume (42%) over the base model. The final model for clearance and volume parameters was clearance = 0.854 · (weight/70)^0.75; central volume of distribution = 10.3 · (weight/70)^1.0 · (age/8.5)^−0.267; peripheral volume of distribution = 4.08 · (weight/70)^1.0; and intercompartmental clearance = 5.34 · (weight/70)^0.75. Application of the model to data from a clinical trial in SMA patients suggests altered kinetics, perhaps based on underlying physiologic differences such as alterations in lean body mass. Future studies in SMA should incorporate modeling and simulation techniques to support individualized dosing and further assess if additional patient-specific factors necessitate alternative dosing strategies.