title: Modulators of very low voriconazole concentrations in routine therapeutic drug monitoring.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Arwa
authors.initials: A
authors.lastname: Hassan
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Riedel
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
authors.forename: David
authors.initials: D
authors.lastname: Czock
mesh_terms: D000935:Antifungal Agents / Q000009:adverse effects / Q000097:blood* / Q000378:metabolism* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D004790:Enzyme Induction / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D055118:Medication Adherence; D011110:Polymorphism, Genetic; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood* / Q000378:metabolism* / Q000493:pharmacokinetics; D012189:Retrospective Studies; D016896:Treatment Outcome; D014230:Triazoles / Q000009:adverse effects / Q000097:blood* / Q000378:metabolism* / Q000493:pharmacokinetics; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole