有限采样法监测口服麦考酚钠肠溶片的肾移植受者血麦考酚酸浓度的研究

Limited sampling strategies predicting mycophenolic acid area-under-the-curve in Chinese renal transplant recipients receiving enteric-coated mycophenolate sodium and tacrolimus

目的研究肾移植受者口服麦考酚钠肠溶片（EC-MPS）后血麦考酚酸（MPA）药代动力学特征，并通过有限采样法研究0～12h的药物曲线下面积（AUＣ０－１２ｈ）。方法按照入选和排除标准筛选20例接受EC-MPS＋他克莫司＋泼尼松三联免疫抑制治疗的汉族肾移植受者作为研究对象，在肾功稳定期（肾移植术后21d）监测受者口服EC-MPS后10个时间点（服药药后0．5、1、1．5、2、3、4、6、8、10和12h）的血浆MPA水平，应用Jackknife技术、多元线性回归分析以及Origin专业函数绘图软件（7．5版）来分析计算MPAAUC。结果口服EC-MPS后，20例受者间血浆MPA水平及AUC变异很大。最佳有限采样法有三点法（血MPA浓度检测时间点为1．5、4和8h）和四点法（血MPA浓度检测时间点为1．5、4、6和8h），公式分别为AUCo-12h=12．820＋0．662×C15h＋1．750×C4h＋4．213×C8h以及AUCo-12h=12．119＋0．676×C115h＋1．685×C4h＋1．429XC6h＋2．573×C8h。三点法校整的相关系数（R）=0．861，P〈0．001；四点法校正的相关系数R=0．882，P〈0．001。结论对于采用EC-MPS＋他克莫司＋泼尼松三联免疫抑制方案的汉族肾移植受者，在服药后1．5、4和8h或者1．5、4、6和8h进行有限采样法监测血浆MPA浓度，能够估算EC-MPS的AUC。

Objective To investigate the pharmacokinetic （PK） characteristics of enteric-coated mycophenolate sodium （EC-MPS） and area under the curve （AUC） from 0 to 12 h by limited sampling strategies （LSSs） in de novo kidney transplant patients of Chinese ethnicity. Method The PK data from 20 Chinese renal transplant recipients collected during the maintenance period after transplantation were analyzed retrospectively. Ten blood samples were obtained after EC-MPS was given on the postoperative day 21. Blood concentrations of mycophenolic acid were measured and AUC was estimated using high performance liquid chromatography in recipients receiving immunosuppressant EC-MPS plus tacrolimus and steroid. LSSs with jackknife technique, multiple stepwise regression analysis, and Origin 7. 5 analysis were developed to estimate mycophenolic acid （MPA） AUC. Result There was wide inter-individual variation in MPA plasma level and the AUC. The best equations obtained in the test group were for 3 and 4 time points： AUCo-12h （mg h L-1） = 12. 820 ＋ 0. 662 × C1.5h q- 1. 750 × C4h q- 4. 213 ×Csh, and AUC0-12h （mg h L-1 ） = 12. 119 ＋ 0. 676× C1.5h ＋ 1. 685 × C4h ＋ 1. 429 × C6h ＋ 2. 573 × Csh respectively. When these LSSs were. tested in the validation group, the results were acceptable （R = 0. 861 ,P〈0. 001 for 3 time points, and R = 0. 882, P〈0. 001 for 4 time points）. Conclusion LSSs are useful for MPA AUGya2h estimation in Chinese renal transplantation patients. LSSs using time points at C1. 5h-C4h-C4h - C8b C15h-C4h-C6h-C8 sh provide the most reliable and accurate estimation of the AUC0-12h of mycophenolic acid in Chinese stable renal transplant recipients receiving EC-MPS and tacrolimus.