Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes
Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes
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DOI：
10.1016/j.ijantimicag.2009.01.008
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发表时间：
2009-07-01
影响因子：
10.8
通讯作者：
Yamada, Katsushi
中科院分区：
文献类型：
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作者：
Matsumoto, Kazuaki;Ikawa, Kazuro;Yamada, Katsushi
伏立康唑代谢主要通过细胞色素P450 (CYP) 2C19同工酶介导。非野生型（突变型）CYP2C19通常存在于60-70%的亚洲人群中。由于已有报道称伏立康唑谷血浓度与肝毒性相关，本研究对29例日本真菌感染患者（CYP2C19野生型，n = 10；非野生型，n = 19） CYP2C19多态性对伏立康唑谷血浓度与肝功能异常关系的影响进行了研究。29例谷浓度>= 3.9 mg/L的患者中有10例（34.5%）出现肝毒性，根据国家癌症研究所的标准定义为肝酶异常。Logistic回归分析建议伏立康唑谷浓度的治疗范围为2 ~ 4 mg/L。非线性药代动力学分析提示，日本患者CYP2C19野生型患者起始剂量为7.2 ~ 8.9 mg/kg/d，非野生型患者起始剂量为4.4 ~ 6.5 mg/kg/d。这些推荐的初始剂量和随后通过治疗药物监测对目标浓度范围的剂量调整应避免不良事件，从而使伏立康唑对日本真菌病患者的治疗持续有效。(C) 2009 Elsevier B.V.与International Society of Chemotherapy。版权所有。
Voriconazole metabolism is mostly mediated via the cytochrome P450 (CYP) 2C19 isozyme. The non-wild (mutant) type of CYP2C19 is generally found in 60-70% of Asian populations. Because the voriconazole trough plasma concentration has been reported to correlate with hepatotoxicity, this study investigated the effect of CYP2C19 polymorphism on the relationship between voriconazole trough concentrations and liver function abnormalities in 29 Japanese patients with fungal infections (CYP2C19 wild-type, n = 10; non-wild-type, n = 19). Hepatotoxicity, defined as liver enzyme abnormality according to the National Cancer Institute criteria, was observed in 10 (34.5%) of 29 patients with a trough concentration >= 3.9 mg/L. Logistic regression analysis suggested that the therapeutic range for the voriconazole trough concentration should be 2-4 mg/L. Non-linear pharmacokinetic analysis suggested that voriconazole therapy should be initiated with a dose of 7.2-8.9 mg/kg/day for CYP2C19 wild-type and 4.4-6.5 mg/kg/day for the non-wild-type in Japanese patients. These recommended initial dosages and subsequent dose adjustment for the target concentration range by therapeutic drug monitoring should avoid adverse events and thus enable continued effective voriconazole therapy for Japanese patients with mycoses. (C) 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.