摘要
目的:建立环孢素在再生障碍性贫血患儿中的群体药动学模型,为其临床个体化用药提供依据。方法:回顾性收集94例再生障碍性贫血患儿的194份血药浓度常规监测数据,应用NONMEM(7.2.0)软件建立药动学模型,用一级条件估计及交互作用(FOCE-Ⅰ)估算药动学参数和个体间、个体内变异。定量考察人口学特征、生化指标、血常规指标、合并用药及CYP3A4*18B、CYP3A5*3基因多态性等协变量对药动学参数的影响,采用自举法对最终模型的稳定性进行评价。结果:基础模型选用一房室、一级吸收和一级消除模型。环孢素的群体药动学参数:表观清除率(CL/F)为(29.5±1.3)L/h,表观分布容积(V/F)为(419.4±52.2)L。CL/F和V/F的个体间变异分别为27.8%和0.14%,个体内变异为36.4%和70ng/ml。按照最终模型,仅有年龄对CL/F有显著影响。自举法验证结果表明模型较稳定。结论:本研究建立的再生障碍性贫血患儿的环孢素群体药动学模型可为该群体的临床个体化用药提供依据。
Objective： To establish the population pharmacokinetic models of cyclosporine in children with aplastic anemia in order to provide references for individual therapy. Methods： A total samples of 194 cyclosporine concentrations were retrospectively obtained from 94 children with aplastic anemia. Population pharmacokinetic parameters,inter-individual variation and individual variation were analyzed by NONMEM（7. 2.0） program. The first order conditional estimation with interaction （FOCE-I ）was used to build the pharmacokinetic model. The impact of covariates including demographic characteristics, biochemical indexes, hematological indexes, coadministration of drugs and genetic polymorphisms of CYP3A4 s 18B and CYP3A5 ＊ 3 on pharmacokinetics were evaluated quantitatively. In addition, the stability of the final model was validated by a nonparametric bootstrap method. Results： One-compartment model with first order absorption and first order elimination was fitted to the basic model. Apparent clearance （CL/F） and apparent volume of distribution （V/F） of cyclosporine were （29.±5_＋ 1.3） L/h and （419.4±52.2） L,respectively. The inter-individual variations of CL/F and V/F were 27.8% and 0.14% ,respectively. The residual variations were 36.4% and 70 ng/ml. Age was identified as the only one significant covariate for CL/F in the final model. The final model was proved to be stable. Conclusion： The population pharmacokinetic model of cyclosporine provides references for clinical individual therapy of cyclosporine in children with aplastic anemia.
出处
《药学服务与研究》
CAS
CSCD
2012年第3期212-216,共5页
Pharmaceutical Care and Research
基金
江苏省苏州市科技项目(No.SYS201001)
江苏省医学重点人才项目(No.RC2007082)
关键词
环孢素
群体药动学
再生障碍性贫血
儿童
cyclosporine
population pharmacokinetics
aplastic anemia
children
