有限取样法估算中国肝移植患者服用霉酚酸钠肠溶片后霉酚酸及其代谢物的体内暴露量  

Limited sampling strategy for estimation of mycophenolic acid and its glucuronide metabolites exposure in liver transplant recipients receiving enteric-coated mycophenolate sodium

作　　者：陆佳倩 刘晓雪[1] 陈皓[2] 陈冰[1] LU Jiaqian;LIU Xiaoxue;CHEN Hao;CHEN Bing(Department of Pharmacy;Organ Transplantation Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China)

机构地区：[1]上海交通大学医学院附属瑞金医院药剂科,上海200025 [2]上海交通大学医学院附属瑞金医院器官移植中心,上海200025

出　　处：《中国临床药学杂志》2018年第1期8-15,共8页Chinese Journal of Clinical Pharmacy

基　　金：上海市自然科学基金(编号12ZR1418900);国家自然科学基金(编号81473275)

摘　　要：目的建立预测肝移植受者口服霉酚酸钠肠溶片(EC-MPS)后霉酚酸(MPA),以及MPA代谢物(MPAG、Ac MPAG)的体内暴露量的有限取样法(LSS)模型。方法 34例接受EC-MPS+他克莫司+泼尼松三联免疫抑制治疗的中国肝移植受者,共采集49例次术后21 d内患者口服EC-MPS前即刻及服药后0.5、1、1.5、2、2.5、3、4、8、12 h全血标本,采用LC-MS/MS法测定血浆中MPA及MPAG、Ac MPAG浓度。采用多元线性回归分析法,获得包括1~4个浓度估算MPA AUC的LSS模型,计算预测误差,Bland-Altman分析法用于评价预测值和实测值的一致性,并采用bootstrap法对初选模型进行内部验证。同时,评估采用LSS法预测MPAG和Ac MPAG体内暴露的效果。结果最佳有限取样法有三点法(2、3和8 h)和四点法(1.5、2.5、3和6 h),对应的MPA预测模型为:MPA AUC_(0→12h)=7.22+0.54×ρ2+2.32×ρ3+5.74×ρ8(R^2=0.79),AUC_(0→12h)=10.78+1.13×ρ1.5+0.50×ρ2.5+1.37×ρ3+3.32×ρ6(R^2=0.84);对应的MPAG和Ac MPAG模型R^2均>0.90。结论对于采用EC-MPS+他克莫司+泼尼松三联免疫抑制方案治疗的肝移植受者,在服药后2、3和8 h或者1.5、2.5、3和6 h进行有限取样法监测血浆MPA及其代谢物浓度,能够估算EC-MPS给药后MPA、MPAG、Ac MPAG的AUC_(0→12h)值,可用于预测患者给药后MPA及其代谢物体内暴露。AIM To develop limited sampling strategy （LSS） for accurate prediction of the exposure for both mycophenolic acid （MPA） and its glucurenide metabolites in liver transplant recipients treated with enteric- coated mycophenolate sodium （EC-MPS）. METHODS Totally 35 liver transplant recipients were treated with EC-MPS, tacrolimus and prednisone. Plasma MPA, mycophenolic acid glucuronide（MPAG） and acyl mycophenol- ic acid glucuronide （AcMPAG） concentration （ totally 49 cases） was measured before medication, 0.5, 1,2.5, 2, 2.5,3,4, 8 and 12 h after medication using LC-MS/MS. Multiple linear regression analysis was used to determine 1 -4 sampling estimation models. The selected models were validated by bootstrap procedure and Bland-Altman a- nalysis. According to the sampling time of MPA selected models, the MPAG AUC and AcMPAG AUC models were established by multiple linear regression analysis. RESULTS The best equations obtained were for 3 and 4 time points ： MPA AUC0→12 h = 7.22 ＋ 0.54 × p2 ＋ 2. 32× p3 ＋ 5.74 × p8 （R2 = 0. 79 ）, AUC0→12h = 10. 78 ＋ 1. 13 × p1.5 ＋ 0.50 × p2.5 ＋ 1.37 x p3 ＋ 3.32 × p6 （R2 = 0. 84）. In addition, corresponding MPAG and AcMPAG mod- els had good prediction performance（R^2〉 0.90 ）. CONCLUSION Limited sampling strategy models using time points atp2 -p3 -p8 orp1.5 -p2.5 -p3 -p6 provide the most reliable and accurate estimation of the AUC0_.1： h of MPA and its glueuronide metabolites in Chinese liver transplant reeiplents receiving EC-MPS.

关 键 词：有限取样法 肝移植 霉酚酸钠肠溶片 霉酚酸 霉酚酸葡糖苷酸 霉酚酸酰基葡萄糖苷 

分 类 号：R969[医药卫生—药理学]