Katada Yoshiki, Hira Daiki, Umemura Keisuke, Katsube Yurie, Ishimura Hiroki, Kojima Yusuke, Hirai Machiko, Kajiwara Moto, Sugimoto Mitsuhiro, Endo Hiroki, Cao Junru, Ohta Saki, Kotani Kinuka, Hatazoe Sakiko, Tsuda Masahiro, Nakagawa Shunsaku, Shinohara Koh, Tsuchido Yasuhiro, Nagao Miki, Terada Tomohiro
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
Department of Infection Control and Prevention, Kyoto University Hospital, Kyoto, Japan.
Clin Transl Sci. 2025 Aug;18(8):e70317. doi: 10.1111/cts.70317.
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.
伏立康唑（VRCZ）是一种具有广谱抗真菌活性的三唑类抗真菌药物。它由肝细胞色素P450（CYP）同工酶CYP2C19代谢，其基因多态性导致药物疗效和安全性存在显著差异。CYP2C19的代谢不良等位基因在亚洲人群中更为常见，增加了VRCZ血药浓度高于治疗水平的风险。我们基于CYP2C19基因多态性开发了一种新型列线图。本研究旨在评估CYP2C19基因型指导的VRCZ治疗是否能降低日本患者的毒性。这项回顾性研究纳入了64例患者（基因型指导组，n = 26；对照组，n = 38）。主要结局定义为VRCZ常见不良事件的综合发生率，以≥2级肝毒性和视觉症状的联合发生为代表。次要结局包括将VRCZ谷浓度维持在治疗范围内（1 - 4μg/mL）的患者比例以及28天时的治疗反应。基因型指导组不良事件的综合发生率显著低于对照组（p = 0.003）。对照组有9例患者（23.7%）因不良事件停用VRCZ，基因型指导组有1例患者（3.8%）停用（p = 0.039）。在初始采样点，基因型指导组有更多患者的血药浓度达到治疗范围。然而，两组间的治疗反应率无显著差异。基于CYP2C19基因分型的VRCZ给药改善了治疗谷浓度管理，在维持治疗效果的同时降低了不良反应。这些发现凸显了CYP2C19基因分型在日本患者VRCZ治疗中的重要性。
