【作者】 芮建中； 仇向华； 张弋； 沈中阳； 李金恒；

【Author】 QIU Xiang-hua~1,ZHANG Yi~2,SHEN Zhong-yang~2,RUI Jian-zhong~1,LI Jin-heng~1 1 Department of Pharmacology,Nanjing General Hospital of Nanjing Military Command,PLA,Nanjing 210002,Jiangsu;2Center 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9.96 L/h、85.9 L、36.7 L/h、351 L、2.53 h^-1和0.242 h。CL/F、V₃和Q群体典型值的最终回归方程分别为:C（?）/F=9.96×（DD/2）^0.887×（AGE/32）^-0.654×（POD/15）^0.216、（?）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:CL/F = 9.96×（DD/2）^0.887×（AGE /32）^-0.654×（POD/15）^0.216,V₂=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