CYP2C19-Guided Voriconazole Therapy: A Precision Medicine Approach to Mitigate Adverse Effects in Japanese Patients

Abstract

Voriconazole (VRCZ) is a triazole antifungal agent with a broad antifungal spectrum. It is metabolized by hepatic cytochrome P450 (CYP) isozyme CYP2C19, whose genetic polymorphism causes significant variability in drug efficacy and safety. Poor metabolizer alleles of CYP2C19 are more common in Asian populations, increasing the risk of supratherapeutic VRCZ levels. We have developed a novel nomogram based on CYP2C19 genetic polymorphisms. This study aimed to evaluate whether CYP2C19 genotype-guided VRCZ therapy reduces toxicity in Japanese patients. This retrospective study included 64 patients (genotype-guided group, n = 26; comparison group, n = 38). The primary outcome was defined as the composite incidence of adverse events commonly observed with VRCZ, represented by the combined occurrence of grade ≥ 2 hepatotoxicity and visual symptoms. Secondary outcomes included the proportion of patients maintaining VRCZ trough concentrations within the therapeutic range (1-4 μg/mL) and the treatment response at 28 days. The composite incidence of adverse events was significantly lower in the genotype-guided group than in the comparison group (p = 0.003). VRCZ discontinuation due to adverse events occurred in nine patients (23.7%) in the comparison group and one (3.8%) in the genotype-guided group (p = 0.039). More patients in the genotype-guided group were achieved through concentrations within the therapeutic range at the initial sampling point. However, treatment response rates did not differ significantly between the groups. VRCZ administration based on CYP2C19 genotyping improved therapeutic trough levels management and reduced adverse effects while maintaining therapeutic efficacy. These findings highlight the importance of CYP2C19 genotyping for VRCZ treatment in Japanese patients.

Keywords: CYP2C19; genotype‐guided; pharmacogenomics; precision medicine; therapeutic drug monitoring; voriconazole.

FIGURE 1

(A) Percentage of patients in each group who continued VRCZ therapy. p‐values, hazard ratios, and 95% confidence intervals (CIs) are displayed in the top‐right corner of the graph. The number of patients at risk of fungal infections at 0, 10, 20, 30, 40, 50, 60, 70, 80, and 90 days after VRCZ initiation is listed at the bottom of the graph. (B) Time to onset of composite adverse events for the comparison and genotype‐guided groups. p‐values, hazard ratios, and 95% confidence intervals (CIs) are displayed in the top‐right corner of the graph. The number of patients at risk of fungal infections at 0, 10, 20, 30, 40, 50, 60, 70, 80, and 90 days after VRCZ initiation is listed at the bottom of the graph.

FIGURE 2

(A, B) Comparison of voriconazole (VRCZ) trough concentrations after treatment initiation between the comparison and genotype‐guided groups. (A) Initial VRCZ trough concentrations (3–5 days after initiation) in the comparison and genotype‐guided groups. (B) Average VRCZ trough concentration after the initial therapeutic drug monitoring (TDM) in the comparison and genotype‐guided groups. The solid lines in panels A and B indicate the median VRCZ trough concentration, while the dotted lines represent the therapeutic range for VRCZ. White circles represent normal metabolizers, white triangles represent rapid metabolizers, white squares represent intermediate metabolizers, and white diamonds represent poor metabolizers in the genotype‐guided group. (C, D): Percentages of patients with VRCZ trough concentration < 1 μg/mL, 1–4 μg/mL, and > 4 μg/mL in the comparison and genotype‐guided groups. (C) Percentages of patients with an initial VRCZ trough concentration of < 1 μg/mL, 1–4 μg/mL, and > 4 μg/mL in the comparison (black bar) and genotype‐guided (white bar) groups. (D) Percentages of patients with average VRCZ trough concentrations after initial TDM < 1 μg/mL, 1–4 μg/mL, and > 4 μg/mL in the comparison (black bar) and genotype‐guided (white bar) group.