Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Organ Transplantation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Clin Pharmacol. 2019 Apr;59(4):578-589. doi: 10.1002/jcph.1352. Epub 2018 Dec 10.
The aim of the present study is to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA) and limited sampling strategy models for the estimation of MPA exposure in Chinese adult renal allograft recipients following oral administration of enteric coated mycophenolate sodium (EC-MPS). A total of 74 sets of full pharmacokinetic profiles and 47 sets of MPA-sparing samples were collected from 102 renal transplant recipients who received oral EC-MPS. The MPA concentration was determined by an enzyme-multiplied immunoassay technique, and the pathophysiologic data were recorded. The PPK model was constructed using nonlinear mixed-effects modeling, and the limited sampling strategy models for MPA were established by using multiple regression analysis and the maximum a posteriori Bayesian assay based on 2 to 4 sampling time points following EC-MPS administration. The pharmacokinetics of MPA were best described by a 2-compartment model with a first-order absorption process and a lag time of absorption. The clearance of MPA was 12.3 ± 1.14 L/h. Comedicating with cyclosporine A was found to have a significant impact on the clearance/bioavailability of MPA (P < .01). Sampling strategies consisted of plasma concentration at 1.5, 2, 4 (C1.5-C2-C4) hours and 1.5, 2, 4, 6 (C1.5-C2-C4-C6) hours after EC-MPS administration were shown to be suitable for the estimation of the MPA area under the concentration-time curve in these patients. The PPK model was acceptable and can describe the pharmacokinetics of MPA in Chinese renal transplant recipients administered EC-MPS. The area under the concentration-time curve of MPA in Chinese renal transplant recipients could be estimated through a limited sampling strategy method, based on which individualized immunosuppressive regimens could be designed.
本研究旨在建立霉酚酸（MPA）的群体药代动力学（PPK）模型，并建立限采样策略模型，以估算中国成年肾移植受者口服肠溶剂型麦考酚钠（EC-MPS）后 MPA 的暴露情况。共收集了 102 例接受口服 EC-MPS 治疗的肾移植受者的 74 组全药代动力学谱和 47 组 MPA 节省样本。MPA 浓度采用酶联免疫测定技术测定，并记录病理生理数据。使用非线性混合效应模型构建 PPK 模型，并基于 EC-MPS 给药后 2 至 4 个采样时间点，使用多元回归分析和最大后验贝叶斯检测建立 MPA 的限采样策略模型。MPA 的药代动力学最好用一个两室模型描述，该模型具有一个一级吸收过程和一个吸收滞后时间。MPA 的清除率为 12.3±1.14 L/h。与环孢素 A 合用对 MPA 的清除率/生物利用度有显著影响（P<0.01）。结果表明，在 EC-MPS 给药后 1.5、2、4 小时（C1.5-C2-C4）和 1.5、2、4、6 小时（C1.5-C2-C4-C6）时采集血浆浓度的采样策略适合于估计这些患者的 MPA 浓度-时间曲线下面积。PPK 模型是可以接受的，可以描述中国肾移植受者给予 EC-MPS 后 MPA 的药代动力学。通过限采样策略方法可以估算中国肾移植受者的 MPA 浓度-时间曲线下面积，在此基础上可以设计个体化的免疫抑制方案。
