A case-report of unpredictable and massive voriconazole intoxication in a patient with extensive CYP2C19 and CYP2C9 polymorphisms.

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.