Department of Pharmacy, Peking University Third Hospital, Beijing, China; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Centre, Beijing, China.
Department of Pharmacy, Peking University Third Hospital, Beijing, China.
Clin Ther. 2019 Jun;41(6):1151-1163. doi: 10.1016/j.clinthera.2019.04.027. Epub 2019 May 10.
The objective of this study was to characterize the population pharmacokinetics of voriconazole and to identify factors that significantly affect pharmacokinetic parameters and to further investigate optimal dosage regimens in Chinese adult patients with hematologic malignancies.
A prospective population pharmacokinetic analysis was performed on 186 concentration measurements obtained from 41 adult patients with hematologic malignancies. All enrolled patients were treated with voriconazole for diagnosed or suspected invasive fungal diseases. Oral voriconazole was routinely administered at a maintenance dose of 200 mg q12h. Serial blood samples were collected after steady-state of each patient. Monte Carlo simulation was applied to optimize dosage strategies.
A one-compartment model with first-order absorption and elimination adequately described the data. The typical voriconazole clearance was 4.18 L/h, the volume of distribution was 88.9 L, and the absorption rate constant was 0.729 h. Clearance and steady-state exposure (AUC) were found to be significantly associated with age and CYP2C19 phenotype. The average AUC of elderly patients (aged 60-90 years) was 2.1 times higher than that of relative younger patients (aged 18-59 years). The average AUC of poor metabolizers (PMs) was approximately 2.5 and 1.8 times higher than that of extensive and intermediate metabolizers (IMs), respectively. Considering both efficacy and tolerability, dosage regimens of 100 and 50 mg orally administered every 12 hours were recommended for elderly IMs and PMs, respectively.
A population pharmacokinetic model for voriconazole in Chinese adult patients with hematologic malignancies was successfully developed and could well capture voriconazole's pharmacokinetic characteristics. Age and CYP2C19 phenotype were found to significantly influence voriconazole clearance and should be taken into consideration clinically for dose optimization. The optimal dosage strategies in specific clinical scenarios were proposed in this study based on model simulation. Because of the high incidence of mutant CYP2C19*2 and *3 alleles, genetic testing seems to be necessary for Asian elderly patients when voriconazole treatment is initiated.
本研究旨在描述伏立康唑的群体药代动力学特征，确定显著影响药代动力学参数的因素，并进一步研究中国血液病成年患者中伏立康唑的最佳剂量方案。
对 41 例血液病确诊或疑似侵袭性真菌感染的成年患者的 186 个浓度测量值进行前瞻性群体药代动力学分析。所有入组患者均接受伏立康唑治疗。常规给予维持剂量 200mg，每 12 小时口服一次。在每个患者的稳态后采集系列血样。采用蒙特卡罗模拟优化剂量方案。
一个具有一级吸收和消除的一室模型充分描述了数据。伏立康唑的典型清除率为 4.18L/h，分布容积为 88.9L，吸收速率常数为 0.729h。清除率和稳态暴露（AUC）与年龄和 CYP2C19 表型显著相关。老年患者（60-90 岁）的 AUC 平均值是相对年轻患者（18-59 岁）的 2.1 倍。弱代谢者（PM）的 AUC 平均值分别约为广泛代谢者（IM）和中间代谢者（IM）的 2.5 倍和 1.8 倍。考虑到疗效和耐受性，对于老年 IM 和 PM，建议口服 100mg 和 50mg，每 12 小时一次。
成功建立了中国血液病成年患者伏立康唑的群体药代动力学模型，能够很好地捕捉伏立康唑的药代动力学特征。年龄和 CYP2C19 表型被发现显著影响伏立康唑的清除率，在临床中应考虑进行剂量优化。本研究基于模型模拟提出了特定临床情况下的最佳剂量策略。由于 CYP2C19*2 和 *3 等位基因突变的发生率较高，亚洲老年患者在开始伏立康唑治疗时似乎需要进行基因检测。
