Voriconazole (VRCZ) is a potent antifungal agent used to treat invasive fungal infections. However, its clinical utility is limited by the large inter-individual variability in blood concentrations and narrow therapeutic window, which contributes to toxicity and treatment failure. A key factor is genetic polymorphisms in CYP2C19, a hepatic enzyme responsible for VRCZ metabolism. Notably, loss-of-function alleles of CYP2C19 are far more prevalent in Asian populations, including the Japanese population.

We evaluated the impact of genotype-guided VRCZ dosing strategy in Japanese patients. By integrating CYP2C19 genotyping into routine clinical care at Kyoto University Hospital, we aimed to personalize the initial VRCZ dosing prior to therapeutic drug monitoring. This approach significantly reduced the incidence of adverse effects, particularly hepatotoxicity and visual disturbances, compared to standard label-based dosing. In addition, more patients reached therapeutic trough concentrations early in therapy, potentially improving treatment continuity without compromising efficacy.

Our findings support the incorporation of CYP2C19 genotyping into routine clinical practice to enhance the safety and precision of VRCZ therapy, particularly in populations with high prevalence of poor metabolizer alleles. Importantly, our study presents a novel, clinically applicable dosing nomogram specifically designed for CYP2C19 poor metabolizers—an area where the current CPIC guidelines do not provide specific dosing recommendations. By offering a practical tool to guide initial VRCZ dosing in these high-risk patients, our work advances the implementation of pharmacogenomics in infectious disease therapeutics and helps close the critical gap in precision antifungal therapy.

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