Modulators of very low voriconazole concentrations in routine therapeutic drug monitoring

Very low voriconazole concentrations are commonly observed during therapeutic drug monitoring. Possible mechanisms include inappropriate dose selection, rapid metabolism (as a result of genetic polymorphisms or enzyme induction), and also nonadherence. We aimed to develop a method to distinguish between rapid metabolism of and nonadherence to voriconazole by quantification of voriconazole metabolites. In addition, the relevance of common genetic polymorphisms of CYP2C19 was assessed. In a retrospective study, samples with voriconazole concentrations 0.2 μg/mL or less in routine therapeutic drug monitoring (as quantified by high-performance liquid chromatography) were evaluated. Voriconazole and its N-oxide metabolite were quantified in residual blood using a highly sensitive liquid chromatography-tandem mass spectroscopy method (lower limit of quantitation = 0.03 μg/mL). Genetic polymorphisms of CYP2C19 were determined by real-time polymerase chain reaction using the hybridization probe format and the polymerase chain reaction-random fragment length polymorphism format. A total of 747 routine therapeutic drug monitoring plasma/blood samples of 335 patients treated with systemic voriconazole were analyzed and in 18.7% of all samples, voriconazole concentrations 0.2 μg/mL or less were found. In 32 samples (30 patients) with adequate dosage and timing of blood withdrawal, nonadherence was strongly suspected in seven patients because voriconazole-N-oxide concentrations were below 0.03 μg/mL, which was not observed in a reference group of 51 healthy volunteers with controlled drug intake. In 10 patients, of whom EDTA blood was available, the ultrarapid metabolizer genotype (CYP2C19*1*17, CYP2C19*17*17) was found in 80% and its prevalence was significantly higher as compared to a reference group (P = 0.02). In conclusion, quantification of voriconazole-N-oxide allowed for detection of suspected nonadherence in one of four patients with very low voriconazole concentrations. In the remaining patients, ultrarapid metabolism resulting from the CYP2C19*17 polymorphism appears to play a major role. Thus, in the case of voriconazole therapy failure, both nonadherence and genetic factors have to be considered.