Published population pharmacokinetic models of valproic acid in adult patients: a systematic review and external validation in a Chinese sample of inpatients with bipolar disorder

Background This study reviewed all published valproic acid (VPA) population pharmacokinetic (PPK) models in adult patients and assessed them using external validation methods to determine predictive performance.Methods Thirteen published PPK models (labeled with letters A to M) not restricted to children were identified in PubMed, Embase, and Web of Science databases. They were evaluated in a sample totaling 411 serum concentrations from 146 adult inpatients diagnosed with bipolar disorder in a Chinese hospital. Serum concentrations of VPA were analyzed by validated ultra-performance liquid chromatography-tandem mass spectrometry. Performance was assessed by four tests (prediction-based diagnostics, visual predictive checks, normalized prediction distribution error, and Bayesian forecasting).Results Models K and L, developed in large samples of Chinese and Thai patients, showed good performance in our Chinese dataset. Models H and J demonstrated good performance in 2 and 3 of the 4 tests, respectively. Another seven models exhibited intermediate performance. The models with the worst performance, F and M, could not be improved by Bayesian forecasting.Conclusion In our validation study, the most important factors contributing to good performance were absence of children, Asian ethnicity, one-compartment models, and inclusion of body weight and VPA dose in previously published models.