CYP2C19 polymorphisms and therapeutic drug monitoring of voriconazole: are we ready for clinical implementation of pharmacogenomics?

Abstract

Since its approval by the U.S. Food and Drug Administration in 2002, voriconazole has become a key component in the successful treatment of many invasive fungal infections including the most common, aspergillosis and candidiasis. Despite voriconazole's widespread use, optimizing its treatment in an individual can be challenging due to significant interpatient variability in plasma concentrations of the drug. Variability is due to nonlinear pharmacokinetics and the influence of patient characteristics such as age, sex, weight, liver disease, and genetic polymorphisms in the cytochrome P450 2C19 gene (CYP2C19) encoding for the CYP2C19 enzyme, the primary enzyme responsible for metabolism of voriconazole. CYP2C19 polymorphisms account for the largest portion of variability in voriconazole exposure, posing significant difficulty to clinicians in targeting therapeutic concentrations. In this review, we discuss the role of CYP2C19 polymorphisms and their influence on voriconazole's pharmacokinetics, adverse effects, and clinical efficacy. Given the association between CYP2C19 genotype and voriconazole concentrations, as well as the association between voriconazole concentrations and clinical outcomes, particularly efficacy, it seems reasonable to suggest a potential role for CYP2C19 genotype to guide initial voriconazole dose selection followed by therapeutic drug monitoring to increase the probability of achieving efficacy while avoiding toxicity.

Keywords: CYP2C19 polymorphisms; antifungal; genotype-guided dosing; pharmacogenetics; pharmacogenomics; pharmacokinetics; therapeutic drug monitoring; voriconazole.