A Case-report of Unpredictable and Massive Voriconazole Intoxication in a Patient with Extensive CYP2C19 and CYP2C9 Polymorphisms.

Florian Lemaitre (1, 2) , Mathilde Barbaz (3) , Lucie-Marie Scailteux (1) , Fabrice Uhel (2, 3) , Jean-Marc Tadié (2, 3) , Marie-Clémence Verdier (1, 2) , Eric Bellissant (1, 2)

1 Service de Pharmacologie [Rennes]
2 CIC - Centre d'Investigation Clinique [Rennes]
3 Service des maladies infectieuses et réanimation médicale [Rennes] = Infectious Disease and Intensive Care [Rennes]

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.

Keywords: voriconazole; N-oxide voriconazole; toxicology; pharmacokinetics; pharmacogenetics; therapeutic drug monitoring; neurotoxicity

Domains: Life Sciences [q-bio]; Pharmaceutical sciences

Florian Lemaitre, Mathilde Barbaz, Lucie-Marie Scailteux, Fabrice Uhel, Jean-Marc Tadié, et al.. A Case-report of Unpredictable and Massive Voriconazole Intoxication in a Patient with Extensive CYP2C19 and CYP2C9 Polymorphisms.. Drug Metabolism and Pharmacokinetics, 2013, 28 (5), pp.439-41. ⟨10.2133/dmpk.DMPK-13-NT-007⟩. ⟨hal-00910224⟩