Unexpected Voriconazole Overexposure in a CYP2C19 Rapid Metabolizer Due to Inflammation-Induced Phenoconversion: A...

Voriconazole exhibits substantial interindividual pharmacokinetic variability, largely driven by cytochrome P450 enzymes, particularly CYP2C19 and CYP3A4. Although pharmacogenetics plays a key role in predicting voriconazole exposure, systemic inflammation may transiently suppress CYP activity, leading to inflammation-induced phenoconversion. This mechanism can cause clinically relevant drug overexposure even in patients genetically predicted to be normal or rapid metabolizers.

The authors describe the case of an adult patient receiving voriconazole who developed marked drug overexposure despite carrying a CYP2C19 rapid metabolizer genotype. Therapeutic drug monitoring, pharmacogenetic testing, and inflammatory biomarker assessment were performed. Clinical characteristics, laboratory parameters, and voriconazole plasma concentrations were evaluated to determine the impact of inflammation on drug metabolism.

Voriconazole trough concentrations were markedly elevated and inconsistent with the genotype-predicted metabolic profile. This overexposure occurred concomitantly with a significant inflammatory state, reflected by increased C-reactive protein levels. No clinically relevant drug-drug interactions or hepatic dysfunction were identified. As inflammatory markers progressively decreased, voriconazole concentrations declined accordingly, indicating reversible suppression of CYP-mediated metabolic capacity. These findings are consistent with inflammation-induced phenoconversion, whereby cytokine-mediated downregulation of CYP2C19 and CYP3A4 overrides genetically determined enzyme activity.

This case highlights the importance of an integrated approach to voriconazole therapy that combines pharmacogenetics, inflammatory status, and therapeutic drug monitoring. Recognizing inflammation-induced phenoconversion as a dynamic determinant of drug metabolism may improve the safety and efficacy of antifungal treatment.