Case Report: Dual toxicity of voriconazole in a CYP2C19 poor metabolizer: a case analysis of life-threatening neutropenia and hepatocellular injury

Abstract

Background Voriconazole, a first-line therapy for invasive aspergillosis, exhibits variable pharmacokinetics due to CYP2C19 polymorphisms. However, severe hematological toxicity, particularly life-threatening neutropenia, remains under-recognized. The concomitant occurrence of dual severe organ toxicities in CYP2C19 poor metabolizers (PMs) poses a significant clinical challenge. Case We report a case of a 71-year-old Chinese male with invasive pulmonary aspergillosis. After approximately 40 days of oral voriconazole therapy (400 mg q12h loading dose, then 200 mg q12h maintenance), he sequentially developed grade 4 neutropenia (Absolute Neutrophil Count nadir 0.02 × 109/L) with fever and grade 3 hepatocellular liver injury (Alanine Aminotransferase [ALT] peak 738 U/L; R ratio approximately 65.9). Pharmacogenomic testing performed during hospitalization on 27 March 2025 revealed a CYP2C19 *2/*3 PM genotype. Causality assessments using the Naranjo and RUCAM scales rated both events as probable in relation to voriconazole. Following discontinuation of voriconazole, antifungal therapy was sequentially changed to isavuconazonium sulfate, nebulized amphotericin B liposome, and intravenous amphotericin B cholesteryl sulfate complex, together with granulocyte colony-stimulating factor and hepatoprotective therapy. The patient’s neutrophil count and liver function improved, and he was discharged in stable condition with isavuconazonium sulfate capsules 200 mg qd after discharge. After discharge, he reported feeling well but did not undergo follow-up laboratory or imaging examinations. Conclusion This case illustrates a clinical scenario in which pre-emptive pharmacogenomic testing, vigilant monitoring of complete blood counts alongside liver function, and integration with therapeutic drug monitoring (TDM) may enhance safety in patients requiring long-term voriconazole therapy. The absence of TDM data precludes definitive confirmation of voriconazole overexposure; nevertheless, the convergence of CYP2C19 PM genotype, temporal relationship, dechallenge, and structured causality assessment renders presumed drug accumulation the most plausible explanation for the observed toxicities while not excluding all competing contributors.