title: Therapeutic Drug Monitoring and Genotypic Screening in the Clinical Use of Voriconazole.
abstract: Voriconazole is an antifungal triazole that is the first line agent for treatment of invasive aspergillosis. It is metabolized by CYP2C19, CYP2C9, and CYP3A4 and demonstrates wide interpatient variability in serum concentrations. Polymorphisms in CYP2C19 contribute to variability in voriconazole pharmacokinetics. Here, evidence is examined for the use of voriconazole therapeutic drug monitoring (TDM) and the role of CYP2C19 genotyping in voriconazole dosing. The majority of studies exploring the impact of voriconazole TDM on efficacy and safety have found TDM to be beneficial. However, most of these studies are observational, with only one being a randomized controlled trial. High-volume multicenter randomized controlled trials of TDM are currently not available to support definitive guidelines. There is a significant relationship in healthy volunteers between CYP2C19 genotype and voriconazole pharmacokinetics, but this association is markedly less visible in actual patients. While CYP2C19 genotype data may explain variability of voriconazole serum levels, they alone are not sufficient to guide initial dosing. The timeliness of availability of CYP2C19 genotype data in treatment of individual patients also remains challenging. Additional studies are needed before implementation of CYP2C19 genotyping for voriconazole dosing into routine clinical care.
authors.affiliation: NIH Clinical Center, Pharmacy Department, Bethesda, MD.
authors.forename: Brad
authors.initials: B
authors.lastname: Moriyama
authors.affiliation: NIH Clinical Center, Critical Care Medicine Department, Bethesda, MD.
authors.forename: Sameer
authors.initials: S
authors.lastname: Kadri
authors.affiliation: NIH Clinical Center, Pharmacy Department, Bethesda, MD.
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Henning
authors.affiliation: NIH Clinical Center, Critical Care Medicine Department, Bethesda, MD.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Department of Medicine, Pediatrics, and Microbiology and Infectious Diseases, Weill Cornell Medical Center of Cornell University, New York, NY.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
authors.affiliation: Department of Pharmacotherapy University of North Texas System College of Pharmacy, Fort Worth, TX.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Penzak
keywords: CYP2C19; pharmacogenomics; pharmacokinetics; voriconazole