Department of Pharmacy, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China.
Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
J Pharm Sci. 2019 Dec;108(12):3923-3931. doi: 10.1016/j.xphs.2019.09.019. Epub 2019 Sep 25.
Because voriconazole metabolism is highly influenced by liver function, the dose regimen of voriconazole should be carefully assessed in patients with liver cirrhosis. We aimed to identify significant factors associated with plasma concentrations. Blood samples were collected from patients with liver cirrhosis who received voriconazole, and voriconazole concentrations were determined. One-compartment model with first-order absorption and elimination appropriately characterized the in vivo process of voriconazole. The typical population value of voriconazole clearance (CL) was 1.45 L/h and the volume of distribution (V) was 132.12 L. The covariate analysis identified that CYP2C19 gene phenotype and Child-Pugh classification were strongly associated with CL and body weight had a significant influence on V. The results of the Monte Carlo simulation suggested that CYP2C19 gene phenotype was a critical factor for determining voriconazole dosage in patients with liver cirrhosis. The extensive metabolizer patients with Aspergillus fumigatus infections could be treated effectively with a recommended dose of 75 mg twice daily in mild to moderate liver cirrhosis and 100 mg once daily in moderate severe liver cirrhosis. However, the recommended dosage for Candida albicans infections patients was not achieved in present study.
由于伏立康唑的代谢受肝功能影响很大，因此应在肝硬化患者中仔细评估伏立康唑的剂量方案。我们旨在确定与血浆浓度相关的重要因素。采集接受伏立康唑治疗的肝硬化患者的血样，并测定伏立康唑浓度。一房室模型，首过吸收和消除均为一级过程，能很好地描述伏立康唑的体内过程。伏立康唑清除率（CL）的典型人群值为 1.45 L/h，分布容积（V）为 132.12 L。协变量分析表明，CYP2C19 基因表型和 Child-Pugh 分级与 CL 密切相关，体重对 V 有显著影响。蒙特卡罗模拟的结果表明，CYP2C19 基因表型是确定肝硬化患者伏立康唑剂量的关键因素。对于曲霉菌感染的广泛代谢者，在轻度至中度肝硬化中可使用推荐剂量 75mg，每日两次，在中度严重肝硬化中可使用 100mg，每日一次。然而，在本研究中，对于白色念珠菌感染患者，并未达到推荐剂量。
