Physiologically Based Pharmacokinetic Modeling Combined with Clinical Data to Explore the Pharmacokinetics of Voriconazole in Pediatric Patients with Hepatic Impairment

Objectives: To develop a physiologically based pharmacokinetic (PBPK) model of voriconazole for pediatric patients with hepatic impairment, evaluate the effects of varying degrees of hepatic impairment on voriconazole pharmacokinetics, and provide a rational basis for dose optimization. Methods: PBPK models of voriconazole were developed using GastroPlus™ version 9.9. An adult model was first developed and extrapolated to children. Physiological parameters of different hepatic impairment (Child–Pugh class A, B, and C) were then integrated to develop models for both pediatric and adult patients with hepatic impairment. The models were further adjusted and verified using data from pediatric patients with or without hepatic impairment at our hospital, followed by population simulations and pharmacodynamic evaluation. Results: The models demonstrated satisfactory predictive performance. For the literature datasets, the fold error (FE) ranged from 0.6 to 2.0 and the geometric mean fold error (GMFE) < 2.0; for in-hospital datasets, the mean absolute prediction error (MAPE) was 15.13% (normal hepatic function) and 17.27% (hepatic impairment). Simulations showed that area under the concentration-time curve (AUC) increased progressively with worsening hepatic impairment, with increases of 49–83% in Child–Pugh class A and 74–86% in class B compared with normal hepatic function. Pharmacodynamic evaluation showed that at minimum inhibitory concentration (MIC) ≤ 2 mg/L, optimized regimens and the Child-Pugh class C regimen achieved target trough concentrations with probability of target attainment (PTA) ≥ 90% and ≥ 80%, respectively. Conclusions: A PBPK model of voriconazole was successfully developed for pediatric patients with hepatic impairment, which may be useful for providing guidance for individualized dosing.