411例肾移植患者口服环孢素A群体药动学研究

Population pharmacokinetics of oral cyclosporine A in patients post renal transplantation

目的:考察肾移植患者口服环孢素A的群体药动学特征。方法:用NONMEM软件,针对411例门诊肾移植患者(建模组274例,验证组137例)的1 122个时间数据进行群体药动学体内分析。结果:群体最大消除常数典型值(Vm)为:Vm(mg·d-1)=θ1·(DAY／800)θ4·(BW／60)θ6·(AGE／42)θ7·(ALB／40)θ10·(DB／5)θ11·(ALT／20)θ13·(TG／1．8)θ15·θ16(AST>50),或Vm(mg·d-1)=θ1·(DAY／800)θ4·(BW／60)θ6·(AGE／42)θ7·(ALB／40)θ10·(DB／5)θ11·(ALT／20)θ13·(TG／1．8)θ15(AST≤50);米氏常数Km(μg·L-1)=θ2·(DOSE／200)θ3·(DAY／800)θ5·(BW／60)θ6·(AGE／42)θ9·(CR／110)θ12·(ALT／20)θ14;Vm和Km的个体间变异分别是25．4和14．2;个体自身的变异是18．7。结论:肾移植患者每日口服环孢素剂量和术后时间对米-曼氏模型参数影响较大,用群体药动学模型分析常规监测数据可为临床患者提供用药依据。

Objective： To evaluate the population pharmacokinetic profiles of oral cyclosporine A （CsA） in patients post renal transplantation. Methods：1122 steady-state trough CsA concentrations and the associated daily dosage （ mg·d^ -1 ） collected from 411 out-patients post renal transplantation were analyzed using NONMEM program. Michaelis-Menten model was applied as basic pharmacokinetic model. Interindividual and intraindividual variability of Km and Vm were estimated with an additive model. The effect of dosage （DOSE）, period after operation （POD）, body weight （BW）, gender （GEN） and 12 kinds of biochemical index on pharmacokinetic parameters were evaluated using structural parameter models. Results： Michaelis-Menten model was better than one compartment linear mean-steady-state model in routine monitoring steady-state trough concentrations of CsA. The performance group （ n = 137） was predicted better using population pharmacokinetic parameters estimated from index group （n = 274）. The final model and parameters of total data set were as follows： typical Vm（mg·d^-1）=θ1·（DAY/800）^θ·（BW/60）^θ·（AGE/42）^θ·（ALB/40）/40·（DB/5）^θ1·（ALT/20）^θ3·（TG/1.8）^θ5·θ16（AST〉50）,（mg·d^-1）=θ1·（DAY/800）^θ·（BW/60）^θ·（AGE/42）^θ·（ALB/40）^θ0·（DB/5）^θ1·（ALT/20）^θ3·（TG/1.8）^θ5（AST≤50）; Typical gm Km（μg·L-1）=θ2·（DOSE/200）^θ·（DAY/800）^θ·（BW/60）^θ·（AGE/42）^θ·（CR/110）^θ2·（ALT/20）^θ4. The interindividual variability of Vm （ mg· d^- 1 ） and Km（μg·L-1） were 25.4 and 14.2, respectively . The intraindividual variability （μ·L^-1） was 18.7. The mean absolute percent error of steady-state trough CsA concentrations between predicted and observed values were （7.12 ± 6. 40）% （0.00% ～ 81.65% ）. Conclusion： Daily dosage and period of oral CsA after renal transplantation significantly contributed to Michaelis-Menten model parameters. A good fitness was derived from the population model, which provides a new approach for dosage adjustment of oral CsA.