Understanding variability with voriconazole using a population pharmacokinetic approach: implications for optimal dosing

Objectives: Voriconazole exhibits highly variable, non-linear pharmacokinetics and is associated with a narrow therapeutic range. This study aimed to investigate the population pharmacokinetics of voriconazole in adults, including the effect of CYP2C19 genotype and drug–drug interactions. Methods: Non-linear mixed effects modelling (NONMEM) was undertaken of six voriconazole studies in healthy volunteers and patients. Dosing simulations to examine influential covariate effects and voriconazole target attainment (2–5 mg/L) stratified by CYP2C19 phenotype were performed. Results: We analysed 3352 voriconazole concentration measurements from 240 participants. A two-compart-ment pharmacokinetic model with first-order oral absorption with lag time and Michaelis–Menten elimination best described voriconazole pharmacokinetics. Participants with one or more CYP2C19 loss-of-function (LoF) alleles had a 41.2 % lower Vmax for voriconazole. Co-administration of phenytoin or rifampicin, St John’s wort or glucocorticoids significantly increased voriconazole elimination. Among patients receiving 200 mg of voricon-azole twice daily, predicted trough concentrations on day 7 were,2 mg/L for oral and intravenous regimens for 72 % and 63 % of patients without CYP2C19 LoF alleles, respectively, with 49 % and 35 % below this threshold with 300 mg twice daily dosing. Conversely, these regimens resulted in 29%, 39%, 57 % and 77 % of patients with CYP2C19 LoF alleles with voriconazole trough concentrations ≥5 mg/L