中国健康受试者单剂量口服阿雷地平的群体药代动力学和剂量比例性

Single-dose population pharmacokinetics and dose proportionality of aranidipine in healthy Chinese subjects

目的建立中国健康受试者单剂量口服阿雷地平的群体药代动力学模型,探索剂量比例性,为临床合理用药提供依据。方法将47例健康中国受试者分为3个剂量组,分别单剂量口服阿雷地平肠溶胶囊5 mg (n=12)、10 mg (n=23)和20 mg(n=12),用非线性混合效应模型(NONMEM)建立群体药代动力学模型,并探讨剂量比例性。结果血浆中阿雷地平血药浓度时间曲线符合二室模型,吸收速率常数、表观清除率、中央室和外周室的分布容积群体典型值分别为0.608/h,748 L·h^-1,211 L和740 L。5,10和20 mg剂量下,阿雷地平体内暴露随着剂量增加成比例增加。结论本研究的阿雷地平群体药代动力学模型稳定、可靠,可以作为阿雷地平个体化治疗的依据。

Objective To characterize aranidipine population pharmacokinetics and dose proportionality in Chinese subjects, to support the proper dosing in Chinese patients. Methods Forty-seven Chinese healthy subjects were enrolled and assigned to take a single oral dose of 5 mg(n=12), 10 mg(n=23), and 20 mg(n=12) aranidipine capsules. Population pharmacokinetic(POPPK) modeling was performed using nonlinear mixed effects modeling(NONMEM), and dose proportionality was investigated. Results Plasma aranidipine concentration-time profiles under fasted state were best described by a two-compartment PK model with first-order absorption. The pharmacokinetic parameters in Chinese healthy subjects were well estimated. Aranidipine absorption rate constant(Ka), apparent clearance(CL/F), volume of distribution in the central compartments(V2/F) and peripheral compartments(V3/F) were 0.608/h, 748 L·h^-1, 211 L and 740 L respectively. AR exposure, expressed in AUC0-t and Cmax, was proportionally increased with dose over the dose range of 5, 10 and 20 mg. Conclusion The POPPK model developed in the present study could provide very useful information for dose optimization and individualization in Chinese patients.