title: A case-report of unpredictable and massive voriconazole intoxication in a patient with extensive CYP2C19 and CYP2C9 polymorphisms.
abstract: This case-report describes a massive voriconazole (VRZ) intoxication in a patient with a poor metabolizer profile, highlighted by low plasma main metabolite concentrations (N-oxide voriconazole), despite an extensive genetic profile for CYP2C19 and CYP2C9. The patient was treated with a therapeutic dose of VRZ but developed a neurotoxicity leading to hallucinations and coma while the plasma concentration of VRZ reached an exceptional level (20.0 µg/mL on day 10 of the treatment). Since neurological disorders diminished in parallel with the decrease of VRZ plasma concentrations, the coma was likely due to VRZ. The VRZ half-life, calculated to 58 h in this patient, was by far higher than the values reported in the literature. While VRZ concentrations slowly decreased, the N-oxide voriconazole concentrations slowly increased from day 15. Hypotheses for this lack of metabolization of VRZ are an inhibition of the metabolism by esomeprazole, a saturation of the metabolism or an enzymatic auto-inhibition of VRZ metabolism but none of these hypotheses have yet been explored. This case-report of unpredictable accumulation of VRZ in a patient without any genetic risk factor is an advocacy for systematic therapeutic drug monitoring of VRZ.
authors.affiliation: Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes University Hospital.
authors.forename: Florian
authors.initials: F
authors.lastname: Lemaitre
authors.forename: Mathilde
authors.initials: M
authors.lastname: Barbaz
authors.forename: Lucie-Marie
authors.initials: LM
authors.lastname: Scailteux
authors.forename: Fabrice
authors.initials: F
authors.lastname: Uhel
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Tadié
authors.forename: Marie-Clémence
authors.initials: MC
authors.lastname: Verdier
authors.forename: Eric
authors.initials: E
authors.lastname: Bellissant
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D016903:Drug Monitoring; D006207:Half-Life; D006801:Humans; D008297:Male; D020258:Neurotoxicity Syndromes / Q000209:etiology; D011743:Pyrimidines / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D014230:Triazoles / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D065819:Voriconazole
chemical_list: D011743:Pyrimidines; D014230:Triazoles; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole