This DGI pertains to the interaction between the cytochrome P450 2C19 (CYP2C19) gene and voriconazole. Voriconazole (brand name Vfend) is used to treat serious fungal infections including but not limited to invasive aspergillosis, candidemia in non-neutropenic patients, disseminated Candida infections, esophageal candidiasis, and infections caused by Scedosporium apiospermum and Fusarium. It belongs to a class of drugs known as triazole antifungals. It works by inhibiting ergosterol synthesis via inhibition of lanosterol 14-αdemethylase. Ergosterol is a component of fungal cell membranes so inhibiting the production of ergosterol stops the growth of fungi. Extensive literature indicates that patients with specific genetic differences in the CYP2C19 gene may require dose adjustments of voriconazole or alternative medications in order to achieve therapeutic benefits.
Information presented on this page is based on evidence provided by the Clinical Pharmacogenomics Implementation Consortium (CPIC®). One goal of CPIC is to provide peer-reviewed, updated, evidence-based, and freely accessible guidelines for implementing the use of pharmacogenomic tests into actionable prescribing decisions for patient care. CPIC guidelines follow standardized formats, include systematic grading of evidence and clinical recommendations, use standardized terminology, are peer-reviewed, and are published in a leading journal (in partnership with Clinical Pharmacology and Therapeutics) with simultaneous posting to cpicpgx.org, where they are regularly updated.
The CYP2C19 (sounds like “sip-2-C-19”) gene encodes the CYP2C19 enzyme, which is a member of the cytochrome P450 enzyme family. There are different CYP2C19 gene versions, or variants, and each has a different effect on how well voriconazole is metabolized in the body. Some variants result in a non-functioning or low-functioning CYP2C19 protein while other variants result in a normal-functioning or hyper-active CYP2C19 protein. Different ‘metabolizer statuses’ are assigned to patients depending on their genetic information. See chart below for a description of each metabolizer status and any implications for treatment.
Patient’s genetic information is reported as a diplotype and this corresponds to a phenotype (i.e. metabolizer status). To see an interpretation table assigning metabolizer status by genetic variant, click here to visit CPIC and scroll down to click and download “CYP2C19 diplotype-phenotype table”. A results interpretation by metabolizer status is located below.
aSuch agents include isavuconazole, liposomal amphotericin B, and posaconazole.*
*Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities.
*Guidelines for treatment based on metabolizer statuses are determined by the Clinical Pharmacogenomics Implementation Consortium (CPIC®).
Genotyping for CYP2C19 was performed within a certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Act of 1988. This validated clinical laboratory developed test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored and the accuracy of the results is determined to be > 99%.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy
This link will take you to the main page on the CPIC website relating to CYP2C19 and Voriconazole. On the site, you will find links to the main guideline publication and all supplementary information including a table that reports variant frequencies across different races/ethnic groups, a table that defines genetic variants, and a table that provides a phenotype interpretation (i.e. metabolizer status). Additionally, examples of point of care clinical decision support can be found at the bottom of the page.
Other drugs with CYP2C19 interactions supported by PREDICT can be found here. Please note that other drugs may have CYP2C19 interactions that are currently not included in the PREDICT test. For more information on drug-gene interactions, please use the search feature on the CPIC website.