【作者】 芮建中； 仇向华； 张弋； 沈中阳； 李金恒；

【Author】 QIU Xiang-hua1,ZHANG Yi2,SHEN Zhong-yang2,RUI Jian-zhong1,LI Jin-heng1 (1. Department of Pharmacology,Nanjing General Hospital of Nanjing Military Command,PLA,Nanjing 210002; 2. Center of Organ Transplantation,First Central Hospital,Tianjin 300192,China)

【机构】 南京大学医学院临床学院(南京军区南京总医院)药理科； 天津市第一中心医院器官移植中心；

【摘要】 目的:考察口服他克莫司(TAC)在肝移植患者中的群体药代动力学(PPK)特征,为调整用药方案和个体化给药提供科学依据。方法:用非线性混合效应模型(NONMEM)程序分析前瞻性收集的22例肝移植患者254份TAC的稳态全血药物浓度样本。一级吸收二房室开放模型能够较好的拟合群体数据,估算清除率(CL/F)、中央室分布容积(V2)、室间清除率(Q)、外周室分布容积(V3)、吸收速率常数(Ka)及滞后时间(ALAG)的个体间变异用加法模型,个体自身变异(残差误差)用指数模型。定量评价剂量(DD)、年龄(AGE)、术后时间(POD)、血清肌酐(CR)、血清总胆红素(TBIL)和合并用药等固定效应(协变量)对TAC药代动力学参数的影响。结果:CL/F、V2、Q、V3、Ka和ALAG的群体标准值分别为9.96L/h、85.9L、36.7L/h、351L、2.53h-1和0.242h。CL/F、V2和Q群体典型值的最终回归方程分别为:CL?/F=9.96×(DD/2)0.887×(AGE/32)-0.654×(POD/15)0.216、V?2=85.9×(CR/40)0.674和Q?=36.7×(TBIL/8)0.627。浓度实测值和个体预测值的平均绝对权重残差为5.98±5.79%。结论:固定效应中剂量、年龄、术后时间对TAC的CL/F是有显著意义的协变量,而血清肌酐和血清总胆红素分别对V2和Q有显著影响。更多还原

【Abstract】 OBJECTIVE:To investigate the population pharmacokinetics (PPK) of tacrolimus(TAC) administered by oral in Chinese patients after liver transplantation for regimen schedule and individual dosage. METHODS:TAC population data were prospectively collected from 22 liver transplantation patients. 254 steady-state blood concentrations of TAC after orally administered were evaluated by NONMEM program. A two-compartment open model with first-order absorption was applied as basic pharmacokinetics model. Inter-individual variability of elimination clearance (CL/F), central volume(V2), inter-compartmental clearance(Q), peripheral volume (V3), absorption rate(Ka) and lag time(ALAG) were estimated with addition model. Intra- individual variability (residual error) was estimated with exponential model. The effect of covariate, such as dosage(DD), AGE, period after operation (POD), serum creatinine(CR), serum total bilirubin(TBIL) and concurrent use of drug on pharmaco- kinetic parameters of TAC were quantitatively fitted with fixed effect model. RESULTS:Standard value of CL/F, V2, Q, V3, Ka and ALAG was 9.96 L/h, 85.9 L, 36.7 L/h, 351 L, 2.53 h-1 and 0.242 h respectively. The final regression equation of population typical value of CL/F, V2 and Q was:C L? /F = 9.96×(DD/2)0.887 × (AGE /32)-0.654×(POD/15)0.216, V? 2=85.9×(CR/40)0.674 and Q? =36.7× (TBIL/8)0.627 respec- tively. The mean absolute weighted residual of TAC concentration between individual predicted values and observed values was 5.98±5.79%. CONCLUSION:DD, AGE, POD appeared to be significant covariates for CL/F. CR and TBIL were significant covariate for V2 and Q respectively.更多还原