【摘要】 目的:建立环孢素(CsA)在再生障碍性贫血(AA)患儿中群体药动学(PPK)模型,获取药动学(PK)参数,优化治疗方案,提高疗效,降低药品不良反应(ADR)。方法:回顾性收集2006-2012年9月我院诊治的489例AA患儿相关临床及CsA药物治疗资料,以其中389例次AA患儿资料通过NONMEM模型建立PPK模型,通过内部和外推验证模型的精度与准确性,基于PPK模型和Bayes反馈法结合CsA血药浓度监测(TDM)获取个体PK参数,制定最优化治疗方案对100例次AA患儿进行临床治疗验证,采用Fisher精确概率法通过逐步Logistic回归分析CsA血药浓度与疗效和发生ADR的相关性。结果:年龄、AST、PLC、CsA剂量等固定效应对PPK的最终模型有显著性影响,最终模型预测CsA血药浓度具有良好的准确性和精密度,本组AA患儿CsA的Ke、Vd、CL、tβ1/2、AUCo～24、AUCo～∞等PPK参数分别为0.07 h-1、150.17 L、10.51 mL·min-1.kg-1、9.75 h、3987.54 h·ng·mL-1、6174.67 h·ng·mL-1;在CsA有效血药浓度范围上限以内血药浓度与治疗有效率呈正相关,超出上限有效率并不随CsA浓度增大而升高,反而增加ADR发生率。结论:通过本文PPK模型结合TDM能准确获取个体药动学参数并预测CsA浓度,为临床制定个体化药物治疗方案提供参考。更多还原

【Abstract】 OBJECTIVE To establish the population pharmacokinetics(PPK) model of cyclosporin A in children suffering from aplastic anemia(AA),and to obtain the individual pharmacokinetic(PK) parameters,optimize the treatment regimens,improve the efficacy and reduce the adverse drug reactions(ADR).METHODS Data were retrospectively collected in our hospital from 489 cases of AA patients’ related clinical basic and CsA medication information since January 2006 to 2012 September.The PPK model was established through the NONMEM model in 389 cases with AA data,and obtaining the individual PK parameters by internal and extrapolation verification model accuracy and based on PPK model and Bayes feedback method combined with CsA therapeutic drug monitoring(TDM),constituted the optimal treatment regimens and clinical treatment verification in 100 cases with AA.The correlation of CsA plasma concentration with efficacy and ADR was analyzed by Fisher exact probability method by stepwise Logistic regression.RESULTS The fixed effects such as Age,AST,PLC,CsA dose and so on had significant influence on the PPK final model.There was good accuracy and precision in prediction of CsA blood drug concentration by the PPK final model.The PPK parameters of Ke,Vd,CL,tβ1/2,AUC0~24 and AUC0~∞ were 0.07 h-1,150.17 L,10.51 mL·min-1·kg-1,9.75 h,3 987.54 h·ng·mL-1 and 6 174.67 h·ng·mL-1.There was positive relationship between the CsA plasma concentrations with efficiency within effective concentration range,the effective rate increased with the increment of concentration.However,when the concentration was above the high limit of effective range,it increased the incidence rate of ADR.CONCLUSION The present study showed that it can accurately obtain the individual pharmacokinetic parameters and prediction of concentration of CsA by the PPK model combining with TDM,to provide reference for the clinic in setting individualized drug regimens.更多还原