Population Pharmacokinetic Models of Voriconazole in Pediatric Patients: A Systematic Review

Background/Objectives: Voriconazole dosing in children is complicated by developmental and nonlinear pharmacokinetics, cytochrome P450 2C19 (CYP2C19) variation, variable oral bioavailability, inflammation, organ dysfunction, and drug interactions. We evaluated the characteristics, reporting completeness, and clinical applicability of pediatric and pediatric-inclusive voriconazole population pharmacokinetic (PopPK) models. Methods: PubMed, EMBASE, the Cochrane Library, Web of Science, and supplementary sources were searched from inception to 12 March 2026. Eligible studies developed a voriconazole PopPK model in patients aged 0-18 years or in a broader population with extractable or interpretable pediatric information. Reporting completeness was assessed using the 32-item Clinical Pharmacokinetic (ClinPK) checklist. Results: Eighteen studies published from 2004 to 2025 were included. Model-development cohorts contained 21-173 participants, and 15 studies reported 108-3336 concentrations. The median ClinPK reporting-completeness score was 82.6% (range, 74.2-90.0%). The included studies comprised one infant-specific, nine pediatric-only, six pediatric-young adult, and two mixed pediatric-adult models. Fifteen studies used parametric nonlinear mixed-effects methods and three used nonparametric methods; 15 selected two-compartment models and three selected one-compartment models. Body size was incorporated in 17 models and CYP2C19 phenotype was the most frequent retained covariate (10 models). Elimination structures, exposure targets, and dosing proposals were heterogeneous, and only one model underwent independent external validation. Conclusions: A population-matched model may support initial dosing, but early therapeutic drug monitoring and iterative Bayesian updating remain necessary. Current evidence does not support a universal pediatric model. Independent external validation and prospective implementation studies are required before routine clinical use.