替考拉宁国外儿童药动学数据在国内儿童中的外推适用性考察和剂量优化

The adaptive investigation of population pharmacokinetics of teicoplanin in Chinese children extrapolated from foreign research and dose optimization

目的:考察替考拉宁国外儿童药动学数据在国内汉族儿童中的跨种族外推适用性,为临床个体化给药提供参考依据。方法:收集85例国内汉族儿童的监测数据和临床资料,参考已发表的国外儿童替考拉宁药动学模型,采用外推方法获取我国汉族儿童群体的药动学模型,用拟合优度(Goodness-of-fit)、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:本研究获取的我国汉族儿童替考拉宁药动学参数为:V1(中央室分布容积)=(7.83±5.14) L,V2(周边室分布容积)=(15.13±9.75) L,CL(表观清除率)=(0.32±0.21) L·h-1,CL2(周边室清除率)=(0.23±0.11) L·h-1。拟合优度、直观预测检验和NPDE结果表明,外推模型稳定,预测结果可靠。模拟结果显示,按说明书6 mg·kg-1,或10 mg·kg-1,每日一次维持剂量给药,稳态谷浓度很难达到15~30 mg·L-1的目标浓度范围,维持剂量应提高为15 mg·kg-1,每日一次。结论:该研究通过模型外推成功获取了替考拉宁在我国汉族儿童群体的药动学参数,模拟结果提示说明书儿童维持剂量偏低。

OBJECTIVE To investgate the applicability of the population pharmacokinetics data of teicoplanin extrapolated from the foreign research in Chinese Han children and to provide a reference for individualized therapeutic regimens.METHODS Clinical data from 84 Chinese Han children were collected.The population pharmacokinetics model of teicoplanin in Chinese Han children was establised by referring to a reported research about the pharmacokinetics of teicoplanin in foreign children.The predictive performance of final model was predicted by goodness-of-fit,VPC and normalized predictive distribution error(NPDE).RESULTS The final typical pharmacokinetic parameters obtained were as follows:V1(volume of the central compartment)=(7.83±5.14)L,V2(volume of the peripheral compartment)=(15.13±9.75)L,CL(total body clearance)=(0.32±0.21)L·h-1,CL2(intercompartmental clearance)=(0.23±0.11)L·h-1.The final model structure indicated the stability and the predictive performance of final model could be accepted by goodness-of-fit,VPC and NPDE.The simulation results showed that the steady-state trough concentration was difficult to reach the target,when the maintenance dose was set at a dose of 6 mg·kg-1 or 10 mg·kg-1 according to the instructions.The maintenance dose should be at a dose of 15 mg·kg-1.CONCLUSION The population pharmacokinetics of teicoplanin in Chinese Han children were obtained by model extrapolation,which suggestedthat the maintenance dose according to the instructions was relatively low.