Aim: Several studies have reported population pharmacokinetic models for phenobarbital (PB), but the predictive performance of these models has not been well documented. This study aims to do external evaluation of the predictive performance in published pharmacokinetic models.
Methods: Therapeutic drug monitoring data collected in neonates and young infants treated with PB for seizure control was used for external evaluation. A literature review was conducted through PubMed to identify population pharmacokinetic models. Prediction- and simulation-based diagnostics, and Bayesian forecasting were performed for external evaluation. The incorporation of allometric scaling for body size and maturation factors into the published models was also tested for prediction improvement.
Results: A total of 79 serum concentrations from 28 subjects were included in the external dataset. Seven population pharmacokinetic studies of PB were identified as relevant in the literature search and included for our evaluation. The model by Voller et al showed the best performance concerning prediction-based evaluation. In simulation-based analyses, the normalized prediction distribution error of two models (those of Shellhaas et al and Marsot et al) obeyed a normal distribution. Bayesian forecasting with more than one observation improved predictive capability. Incorporation of both allometric size scaling and maturation function generally enhanced the predictive performance, with improvement as observed in the model of Vucicevic et al. CONCLUSIONS: The predictive performance of published pharmacokinetic models of PB was diverse. Bayesian forecasting and incorporation of both size and maturation factors could improve the predictability of the models for neonates.
Keywords: external evaluation; extrapolation; phenobarbital; population pharmacokinetic models.
© 2021 British Pharmacological Society.