应用非线性混合效应模型法考察儿童疾病因素对环孢素药动学的影响

Influence of pediatric diseases on cyclosporine pharmacokinetics investigated by non-linear mixed effects model

目的:考察疾病因素对于环孢素A(CsA)在儿童体内药动学的影响,促进个体化用药。方法:收集150例包括再生障碍性贫血(AA)、嗜血细胞综合征(HPS)和难治性肾病综合征(RNS)不同病种患儿的CsA血药浓度数据和临床资料。采用非线性混合效应模型法考察疾病种类因素对于CsA药动学的影响。采用Bayesian最大后验概率法获取并比较CsA在不同病种患者中药动学参数的差异。用拟合优度(goodness-of-fit)、自举法(bootstrap)、直观预测检验法(VPC)、正态化预测分布误差(NPDE)对最终模型的预测性能进行验证。结果:最终模型药动学参数的群体典型值分别为:吸收速率常数(k_a)1.22 h^(-1),吸收时滞时间(T_(lag))0.45 h,表观分布容积(V_d)218.18 L,口服清除率(CL)14.45 L·h^(-1)。拟合优度、自举验证、VPC和NPDE结果表明最终模型稳定,预测结果可靠。模型结构显示只有患者的体质量和AST值是影响CsA清除率的显著性因素。CsA在AA、HPS和RNS患者中的药动学参数差异无显著性(P>0.05)。结论:本研究成功获取了CsA在儿童AA、HPS和RNS患者中的药动学参数,上述疾病因素不会显著影响CsA在儿童体内的药动学过程。

OBJECTIVE To investigate the influence of pediatric diseases on pharmacokinetics of cyclosporine A（CsA）,and facilitate individualized dosage regimens.METHODS CsA whole blood concentrations and clinical data were collected from150 children with different diseases including aplastic anemia（AA）,hemophagocytic syndrome（HPS）and refractory nephrotic syndrome（RNS）.The influence of disease factors on pharmacokinetics of CsA was investigated by a non-linear mixed effects population modelling approach.Bayesian method was used to obtain and compare the differences of pharmacokinetic parameters of CsA in different disease subpopulations.The predictive performance of final model was evaluated by goodness-of-fit,bootstrapping,visual predictive check（VPC）and normalized predictive distribution error（NPDE）.RESULTS The typical population values of pharmacokinetic parameters estimated in final model were as follows：absorption rate constant（k_a）1.22 h^（-1）,absorption lag time（T_（lag））0.45 h,apparent volume of distribution（V_d）218.18 L and oral clearance（CL）14.45 L·h^（-1）.The stability and the predictive performance of final model were accepted by goodness-of-fit,Bootstrapping,VPC and NPDE.The final model structure showed that only the weight and AST of patients were significant factors affecting the CsA clearance.There was not significantly difference in CsA pharmacokinetic parameters in AA,HPS and RNS patients（P0.05）.CONCLUSION The pharmacokinetic parameters of CsA in AA,HPS and RNS patients are obtained from this study respectively,and the disease factors as AA,HPS and RNS do not significantly affect the pharmacokinetics of CsA in children.