Population Pharmacokinetics of Valproic Acid in Patients with Mania: Implication for Individualized Dosing Regimens

PurposeThis study characterized the population pharmacokinetic properties of valproic acid in patients with mania and determined potential factors that affect the pharmacokinetic properties of valproic acid in this population.MethodsRoutine therapeutic drug monitoring of valproic acid concentrations, demographic data, and concomitant medications from 206 hospitalized patients with mania were retrospectively collected from Somdet Chaopraya Institute of Psychiatry and Srithanya Hospital, Thailand. Nonlinear mixed-effect modeling was used for data analysis. Covariate model building was conducted using stepwise forward addition and stepwise backward elimination. The final model was evaluated using bootstrap analysis and normalized prediction distribution error. The results were compared with those previously reported in patients with epilepsy given that there is an evidence of a difference in valproic acid clearance between patients with mania and those with epilepsy.FindingsValproic acid data were adequately described by a 1-compartment model. Significant predictors for valproic acid clearance included valproic acid dose and weight. The population estimates for valproic acid CL/F and V/F were 0.464 L/h and 23.3 L, respectively. Valproic acid clearance obtained from this study did not seem to be significantly different from that of patients with epilepsy.ImplicationsA qualified population pharmacokinetic model for valproic acid in patients with mania was developed. This model could be used to optimize valproic acid therapy in patients with mania. Valproic acid clearance could be predicted from valproic acid dose and weight of patients. This predicted clearance can subsequently be used for individualization of optimum valproic acid maintenance dose.