我国肾移植患者环孢菌素常规监测的群体药代动力学  

Population Pharmacokinetic Modeling of Orally Administered Cyclosporine A from Routine Drug Monitoring Data after Renal Transplantation in Chinese

作　　者：芮建中[1] 李金恒[1] 闵佩青[1] 周燕[1] 储小曼[1] 李国晖[1] 温泉[1] 曹学峰[2] 周一鸿 

机构地区：[1]南京军区南京总医院临床药理科,南京210002 [2]解放军乌鲁木齐军区总医院药剂科,乌鲁木齐830000 [3]解放军148医院药剂科,淄博255300

出　　处：《中国临床药理学杂志》2002年第6期431-437,共7页The Chinese Journal of Clinical Pharmacology

摘　　要：目的:考察肾移植患者口服环孢菌素A（Cyclosporine A,CsA）常规监测的群体药代动力学特征,为临床调整个体用药提供新途径。方法:回顾性收集我院745例门诊肾移植病人的1468个全血稳态谷浓度样本,用NONMEM程序分析其群体药物动力学模型,估算米-曼氏模型参数Km和Vm,Km,Vm的个体间变异,以及个体自身变异采用指数模型。定量地考察日剂量、术后时间、体重、环孢菌素A剂型和合并用药等固定效应对药物动力学参数的影响。结果:环孢菌素A的监测值为稳态谷浓度时,其药代动力学能用米-曼氏模型较好地拟合,用建模组数据获得的群体参数在验证组中有较理想的拟合优度。最终群体药代动力学参数为:群体标准值Vm为601mg·L-1,Km为2120mg·L-1。Vm的结构模型参数:术后时间和体重用指数模型,系数分别为-0.210和0.139;性别和剂型用乘法模型,男性较女性的校正系数为1.078,胶囊剂较水剂的校正系数为0.927。Km的结构模型参数:剂量和术后时间用指数模型,系数分别为-1.67和-0.651;合并应用雷公藤多甙片、保肾片用乘法模型,系数分别为1.170、1.130。每日剂量预测值与观察值的平均绝对百分误差为7.72±6.60％。结论:剂量和术后时间对米-曼模型的参数拟合有非常明显的影响。本文估算的参数误差在相对较小的范围内,模型拟合情况较好。OBJECTIVE: To evaluate the population pharmacokinetic characters of orally administered cyclosporine A (CsA) from routine drug monitoring data after renal transplantation for readjusting individual dosage. METHODS: Routine Monitoring CsA population data retrospectively collected from renal transplantation out-patient were investigated by NONMEM program. There were 1468 steady-state trough CsA concentrations and associated daily dosage (mg.d-1) from 745 outpatients in our hospital. Michaelis-Menten model was applied as basic pharmacokinetic model. Interindividual variability of Km and Vm, and the intraindividual variability were estimated with logarithmic additive model. The effect of dosage (DOSE), period after operation (POD), body weight (BW), preparation (PP), gender(GEN) and concurrent use of drug (DG) on pharmacokinetic parameters were evaluated with structural parameter models. RESULTS: Michaelis-Menten model fitted better than one compartment linear non-steady-state and one compartment linear mean-steady-state model in routine monitoring steady-state trough concentration of CsA. Good fitness was obtained in predictive performance group (n=216) using population pharmacokinetic parameters estimated from index group (n=529). The final model and parameters of total data set were: The typical Vm(mg·d-1)=601× POD-0.21 ×BW0.139 × (1+GEN × 0.0778)×(1-PP × 0.0731), where GEN=0 as female and GEN=1 as male; PP=0 as aromatic water preparation and PP=1 as capsule preparation. The typical Km(mg·L-1) =2120 × (DOSE/235)-1.67× POD-0.651 × (1+DG1× 0.17) × (1+DG2 × 0.13), where DG1=1 as the concurrent use of Tabellae Multiglycosidorum Triptergii; and DG2=1 as comediation of Baoshenpian. The interindividual variability of Km and Vm were 24. 1% and 11.7% respectively. The Intraindividual variability was 13.4%. The mean absolute percent error of steady-state trough CsA concentrations between predicted and observed values were 7.72 ± 6.60%.CONCLUSION: Daily dosage of CsA and period after operation of renal transpl

关 键 词：环孢菌素A 肾移植 群体药代动力学 荧光偏振免疫法 米-曼氏模型 

分 类 号：R699.2[医药卫生—泌尿科学] R979.[医药卫生—外科学]