22例肝移植患者他克莫司的群体药代动力学  

Population pharmacokinetics of tacrolimus in 22 Chinese recipients of liver transplantation

作　　者：仇向华[1] 张弋[2] 沈中阳[2] 芮建中[1] 李金恒[1] 

机构地区：[1]南京军区南京总医院药理科,江苏南京210002 [2]天津市第一中心医院器官移植中心,天津300192

出　　处：《医学研究生学报》2008年第9期915-919,共5页Journal of Medical Postgraduates

基　　金：江苏省卫生厅奥赛康临床药学研究基金资助项目(批准号:P200502);天津市卫生局科技基金资助项目(批准号:02ky15);南京军区南京总医院科研基金资助项目(批准号:2005119)

摘　　要：目的:观察口服他克莫司(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。确定一级吸收二房室开放模型为PPK模型,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(TB IL)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、V2和Q群体典型值的最终回归方程为CL/F=9.96×(DD/2)0.887×(AGE/32)-0.654×(POD/15)0.216、V2=85.9×(CR/40)0.674和Q=36.7×(TB IL/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。Objective： To investigate the population pharmacokinetics （PPK） of oral tacrolimus （TAC） in Chinese recipients of liver transplantation and to obtain evidence for the adjustment of therapeutic regimen and individual medication. Methods： A total of 254 samples of steady-state whole blood concentration were prospectively collected from 22 liver transplantation patients after oral administration of TAC and analyzed by the NONMEM program. A two-compartment open model with first-order absorption was used as the 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 the addition model, and the intra-individual variability （residual error） with the exponential model. Such covariates as dosage （DD）, AGE, period after operation （POD）, serum creatinine （CR）, serum total bilirubin （TBIL） and concurrent use of drug on the pharmacokinetic parameters of TAC were quantitatively fitted with the fixed effect model. Results： The population standard values of CL/F, V2, Q, V3,Ka and ALAG were 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 equations of the population typical values of CL/F, V2 and Q were 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 respectively. 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, and CR and TBIL for V2 and Q , respectively.

关 键 词：他克莫司 肝移植 群体药代动力学 非线性混合效应模型 

分 类 号：R969.1[医药卫生—药理学]