Voriconazole (Vfend) – CYP2C19
Rationale
This drug gene interaction (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®). CPIC provides peer-reviewed, updated, evidence-based, and freely accessible guidelines for implementing pharmacogenomic results into actionable prescribing decisions for providers. CPIC guidelines include standardized terminology and a systematic grading of evidence and clinical recommendations published in a leading journal (Clinical Pharmacology and Therapeutics).
Genetic Variant Information
The CYP2C19 (sounds like “sip-2-see-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 enzyme while other variants result in a normal-functioning CYP2C19 enzyme. Some variants can lead to an increase in CYP2C19 enzyme function. 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.
CYP2C19 metabolizer status |
Variants (genotype) |
Implications for voriconazole |
|---|---|---|
| Poor metabolizer | TWO no-function alleles | Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse effects. |
| Intermediate metabolizer | ONE normal function allele AND ONE no-function allele
OR ONE increased function allele AND ONE no-function allele |
Higher dose-adjusted trough concentrations of voriconazole compared with normal metabolizers. |
| Normal metabolizer | TWO normal function alleles | Normal voriconazole metabolism. |
| Rapid metabolizer | ONE normal function allele AND ONE increase function allele | In patients for whom a rapid metabolizer genotype (*1/*17) is identified, the probability of attainment of therapeutic concentrations is modest with standard dosing. |
| Ultrarapid metabolizer | TWO increased functional alleles | In patients for whom an ultrarapid metabolizer genotype (*17/*17) is identified, the probability of attainment of therapeutic voriconazole concentrations is small with standard dosing. |
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.
Results Interpretation
Voriconazole is a medicine used to treat fungal infections, and your genes can affect how well the drug works. CPIC updates guidelines on how to best use these genetic results to support patient care. To view dosing recommendations for voriconazole based on CYP2C19 phenotypes, click on the most recent guideline publication on CPIC’s website and scroll down to Table 2.
Please review the FDA packet insert for additional clinical considerations such as contradictions as well as dose adjustments based on age, organ function, and drug-drug interactions.
Quality of Results
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%.
Supporting Evidence
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.
Please note that additional drugs may have CYP2C19 interactions. For more information on drug-gene interactions, please use the search feature on the CPIC website.