VORICONAZOLE-INDUCED HEPATOTOXICITY CONCISE UP-TO-DATE REVIEW

Voriconazole is a wide spectrum antifungal used primarily for invasive aspergillosis, an invasive mold infection occurs mostly in immunocompromised patients. Hepatotoxicity is the most common voriconazole-related adverse reaction that leads to treatment discontinuation. Even though reported incidence of hepatic adverse reactions during phase 2 and 3 clinical trials were less than 10%, observational studies in post marketing phase revealed much higher incidence reaching up to 69%. Therefore, the burden caused by hepatotoxicity and interruption of antifungal therapy put immunocompromised patients at serious risk. Currently, there is no biomarker in routine clinical use that can clearly predict susceptibility to voriconazole-induced hepatotoxicity. In effort to identify a predictor, plasma concentrations of voriconazole and cytochrome (CYP) 2C19 genotype/phenotype, which is responsible from substantial inter-individual changes in voriconazole pharmacokinetics, are the most studied subjects. Hepatotoxicity tends to occur at higher concentrations (>4 mg/L), but so far, no significant association has identified in this matter. Although CYP2C19 genotype is strongly associated with voriconazole plasma concentration, current data is insufficient to define a causal relationship between CYP2C19 genotype and voriconazole-induced hepatotoxicity. This article reviews the epidemiology, mechanism, laboratory features of voriconazole-induced hepatotoxicity and current literature investigating the influence of voriconazole plasma concentration and CYP2C19 genetics on voriconazole-induced hepatotoxicity.