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 hematopoietic cell transplantation (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 patients undergoing HCT (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 2-compartment linear elimination model incorporating body weight and cytochrome P450 2C19 phenotype described the data. The ratio of individual voriconazole clearance between weeks 1 and 2 ranged from 0.11 to 3.3 (−9.1 to +3.3-fold change). Incorporation of covariate effects by serum C-reactive protein and albumin levels decreased between-occasion variability of clearance as compared to the model without them (coefficient of variation, 41.2% and 59.5%, respectively) and improved the model fit (P <.05). As significant covariates on voriconazole PK, C-reactive protein and albumin concentrations may potentially serve as useful biomarkers as part of therapeutic drug monitoring.
Bibliographical noteFunding Information:
This work was supported by the Hematology Oncology Pharmacist Association Foundation (M.N.K.), and the Department of Pediatrics, Division of Blood and Marrow Transplant, University of Minnesota (A.R.S.).
The authors acknowledge the assistance of the Clinical Pharmacology Shared Resource of the Masonic Cancer Center, designated by the National Cancer Institute, supported in part by P30 CA77598. The authors gratefully acknowledge the patients and families who participated in this work.
© 2021, The American College of Clinical Pharmacology
- between-occasion variability
- population pharmacokinetics
PubMed: MeSH publication types
- Journal Article