PharmGKB summary: voriconazole pathway, pharmacokinetics

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Voriconazole is a triazole antifungal agent active against a variety of fungi and molds, such as Candida, Aspergillus, Fusarium, Scedosporium, and Cryptococcus spps. It is particularly recommended for pulmonary invasive aspergillosis, an infection that primarily occurs in immunocompromised patients, such as those undergoing organ transplantation or with autoimmune conditions 1,2. Voriconazole and other triazole antifungals work by disrupting the synthesis of a compound found in fungal cell membranes called ergosterol. Disruption of ergosterol synthesis leads to damage to the fungal cell membrane and eventual fungal cell death or inhibition of fungal cell growth 3. Although voriconazole is generally well tolerated and effective, it has a narrow therapeutic window. Drug levels that are too low can decrease efficacy, whereas those that are too high can affect tolerability and safety 2,4. Severe adverse events associated with voriconazole use include hepatotoxicity and effects on the central nervous system; visual disturbances are also common, particularly at higher concentrations of the drug 5. The metabolism and clearance of voriconazole, and consequently the levels of the drug within the body, are influenced by the CYP2C19 genotype. Nongenetic factors that affect voriconazole levels include patient age, sex, liver disease, and concomitant medications 6. Drug labels for voriconazole approved by the US Food and Drug Administration and Health Canada note that individuals who are CYP2C19 poor metabolizers (PMs) show, on average, four-fold higher drug exposure compared with normal (extensive) metabolizers (NMs) 7,8. However, the evidence that supports a direct association between CYP2C19 and toxicity or efficacy is limited. This review will provide an overview of the literature on the pharmacokinetics and pharmacogenetics of voriconazole. A particular focus will be on pharmacogenetics as developments in this area may provide a way to optimize dosing.
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