LAUSR

Voriconazole is a widely used antifungal agent in immunocompromised patients, but its utility is limited by its variable exposure and narrow therapeutic index. Population pharmacokinetic (PK) models have been used to characterize voriconazole PK and derive individualized dosing regimens. However, determinants of temporal within-patient variability of voriconazole PK were not well-established. We aimed to characterize temporal variability of voriconazole PK within individuals and identify predictive clinical factors. This study was conducted as a part of a single-institution, phase I study of intravenous voriconazole in children undergoing HCT (NCT02227797). We analyzed voriconazole PK study data collected at week 1 and again at week 2 after the start of voriconazole therapy in 59 pediatric HCT patients (age <21 years). Population PK analysis using nonlinear mixed effect modeling was performed to analyze temporal within-individual variability of voriconazole PK by incorporating a between-occasion variability term in the model. A two-compartment linear elimination model incorporating body weight and CYP2C19 phenotype described the data. Ratio of individual voriconazole clearance between weeks 1 to 2 ranged from 0.11 to 3.3 (-9.1 to +3.3-fold change). Incorporation of covariate effects by serum C-reactive protein (CRP) and albumin levels decreased between-occasion variability of clearance (coefficient of variation: from 59.5% to 41.2%) and improved the model fit (p<0.05). As significant covariates on voriconazole PK, CRP and albumin concentrations may potentially serve as useful biomarkers as part of therapeutic drug monitoring. This article is protected by copyright. All rights reserved.