药学学报, 2020, 55(12): 2960-2967
引用本文:
魏传梅, 苟春霞, 曹康娜, 刘晓芹, 高菲, 蔺婷婷, 焦正. 中国特发性膜性肾病患者他克莫司群体药动学研究[J]. 药学学报, 2020, 55(12): 2960-2967.
WEI Chuan-mei, GOU Chun-xia, CAO Kang-na, LIU Xiao-qin, GAO Fei, LIN Ting-ting, JIAO Zheng. Population pharmacokinetics of tacrolimus in idiopathic membranous nephropathy patients[J]. Acta Pharmaceutica Sinica, 2020, 55(12): 2960-2967.

中国特发性膜性肾病患者他克莫司群体药动学研究
魏传梅1, 苟春霞1, 曹康娜2,3, 刘晓芹2,4, 高菲1, 蔺婷婷1, 焦正2
1. 滨州医学院附属医院药学部, 山东 滨州 256603;
2. 上海市胸科医院, 上海交通大学附属胸科医院, 上海 200030;
3. 中国药科大学临床药动学实验室, 江苏 南京 211198;
4. 复旦大学附属华山医院, 上海 200040
摘要:
本研究建立他克莫司在特发性膜性肾病(IMN)患者中的群体药代动力学(PPK)模型,并定量考察他克莫司药代动力学的影响因素。收集96名IMN患者的610个常规检测的他克莫司谷浓度数据,采用非线性混合效应模型(NONMEM)考察CYP3A5基因型、年龄、性别、体重、肝肾功能、合用药物等对他克莫司药动学参数的影响,并建立他克莫司群体药动学模型。应用拟合优度图(GOT)、自举法(Bootstrap)和预测值校准的直观预测检验(pc-VPC)对构建的模型进行评价。采用一房室模型描述他克莫司体内变化过程,CYP3A5*1/*3型和*1/*1型表观清除率分别是*3/*3型的1.57倍和1.86倍,合用五酯胶囊患者他克莫司清除率是未合用的73.6%,合用金水宝胶囊患者是未合用的1.2倍。模型评价显示构建的模型稳定,结果可靠。本文临床试验经滨州医学院附属医院伦理委员会批准并在滨州医学院附属医院进行。建立的群体药动学模型较好地描述他克莫司在中国IMN患者体内的药动学特征,为他克莫司的个体化治疗提供依据。
关键词:    特发性膜性肾病      他克莫司      群体药动学      非线性混合效应模型      药物相互作用     
Population pharmacokinetics of tacrolimus in idiopathic membranous nephropathy patients
WEI Chuan-mei1, GOU Chun-xia1, CAO Kang-na2,3, LIU Xiao-qin2,4, GAO Fei1, LIN Ting-ting1, JIAO Zheng2
1. Department of Pharmacy, Binzhou Medical University Hospital, Binzhou 256603, China;
2. Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China;
3. Clinical Pharmacokinetics Laboratory, China Pharmaceutical University, Nanjing 211198, China;
4. Huashan Hospital, Fudan University, Shanghai 200040, China
Abstract:
The goal of this work was to establish a population pharmacokinetics (PPK) model of tacrolimus in idiopathic membranous nephropathy (IMN) patients and to identify potential covariates that influence pharmacokinetic of tacrolimus. A total of 610 data points on the blood concentration of tacrolimus were collected from 96 IMN patients in routine clinical settings. Nonlinear mixed-effect modeling (NONMEM) was used to investigate the effects of CYP3A5 genotype, age, gender, weight, laboratory tests and co-therapy medications on the pharmacokinetic of tacrolimus. The PPK model was evaluated by the goodness-of-fit (GOT), bootstrap and prediction corrected visual predictive check (pc-VPC). The pharmacokinetic of tacrolimus was described by a one-compartment model. The apparent clearance (CL/F) of CYP3A5*1/*3 and *1/*1 were 1.57 and 1.86 times of that of *3/*3, respectively. The CL/F of tacrolimus was 73.6% in patients undergoing co-therapy with Wuzhi capsules, and 1.2 times than that of the patients undergoing co-therapy with Jinshuibao capsules. The evaluation of the model shows that the model is stable and has satisfactory predictive performance. The clinical trial was approved by the Society of Ethics and conducted in Binzhou Medical University Hospital. The established PPK model can describe the pharmacokinetic characteristics of tacrolimus in Chinese patients with IMN, and can facilitate individualized therapy with tacrolimus.
Key words:    idiopathic membranous nephropathy    tacrolimus    population pharmacokinetics    nonlinear mixed effect modeling    drug-drug interaction   
收稿日期: 2020-06-28
DOI: 10.16438/j.0513-4870.2020-1073
基金项目: 山东省医药卫生科技发展计划项目(2017WS041).
通讯作者: 蔺婷婷,Tel:18606490062,E-mail:18606490062@163.com;焦正,Tel:18930841095,E-mail:zjiao@sjtu.edu.cn
Email: 18606490062@163.com;zjiao@sjtu.edu.cn
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