Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China.
J Antimicrob Chemother. 2014 Feb;69(2):463-70. doi: 10.1093/jac/dkt369. Epub 2013 Oct 1.
The objective of this study was to estimate the population pharmacokinetics of voriconazole, to identify the factors influencing voriconazole pharmacokinetics and to identify optimal dosage regimens for attaining target pharmacokinetic/pharmacodynamic indices against Aspergillus and Candida infections in patients with invasive fungal infections (IFIs).
To prospectively quantify the relationships between the pharmacokinetic parameters of voriconazole and covariates, a population pharmacokinetic analysis was conducted on pooled data from 406 samples taken from 151 patients with IFIs. Voriconazole plasma concentrations were measured by HPLC. The following covariates were tested: demographic factors, laboratory data, concomitant medications and CYP2C19 genotype. Monte Carlo simulation was used to evaluate the effectiveness of the currently recommended dosage regimen and to design an optimized pharmacodynamic dosage strategy for voriconazole.
The data were appropriately fit by a one-compartment model with first-order absorption and elimination. The voriconazole clearance (CL) was 6.95 L/h, the volume of distribution (V) was 200 L and the oral bioavailability (F) was 89.5%. CL was significantly associated with age, the serum concentration of alkaline phosphatase and the CYP2C19 genotype. Based on the results of the Monte Carlo stimulation, we concluded that Aspergillus infections could be treated effectively with 200 mg of voriconazole administered intravenously or orally twice daily and that Candida infections could be treated with 300 mg administered orally twice daily or with 200 mg administered intravenously twice daily.
This study showed that optimal voriconazole dosage regimens could be determined successfully with prospective population pharmacokinetic analyses and Monte Carlo simulations.
本研究旨在估算伏立康唑的群体药代动力学，确定影响伏立康唑药代动力学的因素，并确定针对侵袭性真菌感染（IFI）患者中曲霉菌和念珠菌感染的目标药代动力学/药效学指标的最佳剂量方案。
为了前瞻性地量化伏立康唑药代动力学参数与协变量之间的关系，对 151 例IFI 患者的 406 个样本进行了群体药代动力学分析。采用 HPLC 法测定伏立康唑的血浆浓度。对以下协变量进行了测试：人口统计学因素、实验室数据、伴随药物和 CYP2C19 基因型。蒙特卡罗模拟用于评估当前推荐剂量方案的有效性，并设计伏立康唑的优化药效学剂量策略。
数据通过具有一级吸收和消除的单室模型得到了适当的拟合。伏立康唑清除率（CL）为 6.95 L/h，分布容积（V）为 200 L，口服生物利用度（F）为 89.5%。CL 与年龄、碱性磷酸酶血清浓度和 CYP2C19 基因型显著相关。基于蒙特卡罗模拟的结果，我们得出结论，200mg 伏立康唑静脉注射或口服，每日两次可有效治疗曲霉菌感染，300mg 伏立康唑口服，每日两次或 200mg 伏立康唑静脉注射，每日两次可有效治疗念珠菌感染。
这项研究表明，通过前瞻性的群体药代动力学分析和蒙特卡罗模拟可以成功确定最佳的伏立康唑剂量方案。
