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Voriconazole (Vfend) is an antifungal agent approved for treatment of invasive aspergillosis and candidemia/candidiasis, as well as for salvage therapy for infections in patients refractory to or intolerant of other antifungal therapy. The drug inhibits the fungal enzyme 14a-sterol demethylase, a critical step in ergosterol biosynthesis.
Voriconazole is metabolized in the liver primarily by CYP2C19; CYP2C9 and CYP3A4 play limited roles. The primary metabolite is voriconazole N-oxide, which has no antifungal activity. Drug clearance is primarily dependent on hepatic metabolism. The pharmacokinetics of voriconazole is highly variable and nonlinear, which results in an increased dose leading to a greater than proportional increase in serum concentration.
The bioavailability of oral voriconazole is >95%. Approximately 60% of the drug in serum is protein bound. Voriconazole has a volume of distribution of 4.6 L/kg. Most (80%) of the drug is excreted in the urine, exclusively as metabolites.
Adverse effects of voriconazole include visual disturbances, skin rashes, and elevated liver enzyme levels.
Monitoring trough levels of voriconazole is suggested in individuals with reduced liver function, individuals with CYP2C19 polymorphisms associated with poor metabolic function, patients taking other medications that affect CYP2C19 activity, and in patients experiencing potential toxicity.
Monitoring trough levels may be reasonable in patients who are not responding optimally or have drug interactions that may decrease voriconazole levels, or to ensure adequate oral absorption.
Trough levels >6 mcg/mL (and especially >10 mcg/mL) have been associated with toxicity in several reports.
Trough levels <1 mcg/mL have been associated with suboptimal response in several reports.
Voriconazole metabolism may be altered by coadministration of drugs that metabolically induce or inhibit CYP2C19 or by genetic polymorphisms that affect enzyme activity.
Trough level (ie, immediately before next dose) monitoring is recommended.
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