Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Int J Infect Dis. 2011 Nov;15(11):e753-8. doi: 10.1016/j.ijid.2011.06.004. Epub 2011 Aug 9.
Voriconazole is a triazole agent with excellent antifungal activity against Aspergillus species. However, despite its potential advantages, the occurrence of unpredictable toxicities might be critical in immunocompromised patients. The aim of this study was to analyze risk factors for voriconazole-related severe adverse events (SAEs).
This prospective observational study was conducted in Korean patients with hematological malignancies and invasive aspergillosis on intravenous voriconazole therapy between June 2008 and April 2009.
Of the 25 patients enrolled, eight (32%) showed voriconazole-related SAEs, which included hepatotoxicities (n=5), cardiac tachyarrhythmias (n=2), and neurotoxicity (n=1). Sex, age, underlying hematological malignancies, voriconazole dose, the co-administration of a proton pump inhibitor, and CYP2C19 genotype were not found to be related to the occurrence of SAEs. However, trough plasma concentrations of voriconazole were found to be significantly higher in the patients with an SAE: median 6.32 mg/l (interquartile range (IQR) 2.86-9.71 mg/l) vs. median 2.15 mg/l (IQR 0.92-4.00 mg/l); p=0.011. Receiver operating characteristic curve analysis identified a cut-off trough concentration for SAEs of 5.83 mg/l (sensitivity 62.5% and specificity 94.1%). Furthermore, multivariate analysis showed that a trough concentration of ≥ 5.83mg/l was the only significant independent risk factor of an SAE.
This study shows that therapeutic drug monitoring is indicated in patients with a voriconazole-related SAE and that dose adjustment is required if the trough concentration of voriconazole exceeds 5.83 mg/l.
伏立康唑是一种三唑类抗真菌药物，对曲霉菌属具有优异的抗真菌活性。然而，尽管其具有潜在优势，但在免疫功能低下的患者中，不可预测的毒性的发生可能是至关重要的。本研究旨在分析伏立康唑相关严重不良事件（SAE）的危险因素。
本前瞻性观察性研究在 2008 年 6 月至 2009 年 4 月期间对接受静脉伏立康唑治疗的患有血液恶性肿瘤和侵袭性曲霉菌病的韩国患者进行。
在纳入的 25 例患者中，有 8 例（32%）出现伏立康唑相关 SAE，包括肝毒性（n=5）、心脏心动过速（n=2）和神经毒性（n=1）。性别、年龄、基础血液恶性肿瘤、伏立康唑剂量、质子泵抑制剂的联合使用以及 CYP2C19 基因型与 SAE 的发生无关。然而，SAE 患者的伏立康唑谷浓度显著更高：中位数 6.32mg/l（四分位距（IQR）2.86-9.71mg/l）vs. 中位数 2.15mg/l（IQR 0.92-4.00mg/l）；p=0.011。受试者工作特征曲线分析确定了 SAE 的谷浓度截断值为 5.83mg/l（敏感性 62.5%和特异性 94.1%）。此外，多变量分析显示，谷浓度≥5.83mg/l 是 SAE 的唯一显著独立危险因素。
本研究表明，对于出现伏立康唑相关 SAE 的患者，需要进行治疗药物监测，如果伏立康唑的谷浓度超过 5.83mg/l，则需要进行剂量调整。
