A Physiologically Based Pharmacokinetic Model for Voriconazole Disposition Predicts Intestinal First-pass Metabolism in Children

Background and Objectives The effect of ontogeny in drug-metabolizing enzymes on pediatric pharmacokinetics is poorly predicted. Voriconazole, a potent antifungal, is cleared predominantly via oxidative metabolism and exhibits vastly different pharmacokinetics between adults and children. A physiologically based pharmacokinetic (PBPK) model was developed integrating hepatic in vitro metabolism data with physiologic parameters to predict pharmacokinetic parameters of voriconazole in adult and pediatric populations. Methods Adult and pediatric PBPK models integrated voriconazole physicochemical properties with hepatic in vitro data into the models. Simulated populations contained 100 patients (10 trials with 10 patients each). Trial design and dosing was based on published clinical trials. Simulations yielded pharmacokinetic parameters that were compared against published values and visual predictive checks were employed to validate models. Results All adult models and the pediatric intravenous model predicted pharmacokinetic parameters that corresponded with observed values within a 20 % prediction error, whereas the pediatric oral model predicted an oral bioavailability twofold higher than observed ranges. After incorporating intestinal first-pass metabolism into the model, the prediction of oral bioavailability improved substantially, suggesting that voriconazole is subject to intestinal first-pass metabolism in children, but not in adults. Conclusions The PBPK approach used in this study suggests a mechanistic reason for differences in bioavailability between adults and children. If verified, this would be the first example of differential first-pass metabolism in children and adults.