头孢哌酮钠舒巴坦钠在儿童群体中的药动学研究和剂量优化

目的： 考察头孢哌酮在儿童群体中的药动学特征，促进个体化用药。方法： 收集140例患儿的临床资料和血药浓度数据。采用非线性混合效应模型法建立头孢哌酮在儿童群体中的群体药动学模型，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）验证最终模型的预测性能。采用模拟试验评价不同用药方案的合理性。结果： 最终模型评价结果表明模型稳定、预测结果可靠，得到的头孢哌酮药动学参数为：表观分布容积（V_d）0.86 L，清除率（CL）0.38 L·h^-1。模型结构显示患儿的体质量及肾小球滤过率是影响药动学参数的显著性因素。基于此模型最终确定各年龄段儿童的最优给药方案为：针对大肠埃希菌，新生儿患者为30 mg·kg^-1，qid，静滴2 h；1个月~2岁患儿为20 mg·kg^-1，qid，静滴2 h；2~14岁患儿为10 mg·kg^-1，tid，静滴2 h；针对肺炎克雷伯菌，新生儿患者为10 mg·kg^-1，tid，静滴2 h；1个月~2岁患儿为10 mg·kg^-1，tid，静滴2 h；2~14岁患儿为10 mg·kg^-1，bid，静滴2 h。结论： 本研究成功建立了头孢哌酮在儿童患者中的药动学模型，并借此模型推导出不同年龄段患儿针对大肠埃希菌及肺炎克雷伯菌的最佳给药方案。

The population pharmacokinetics and dose optimization of cefoperazone sodium and sulbactam sodium in children

OBJECTIVE To investigate the pharmacokinetic characteristics of cefoperazone in pediatric populations and promote individualized medication.METHODS We used the nonlinear mixed effect model to investigate the pharmacokinetic parameters of cefoperazone by the clinical and blood concentration data of 140 children,and the predictive performance of the final model was estimated by goodness-of-fit,visual predictive check(VPC)and normalized predictive distribution error(NPDE).RESULTS The clinical data and plasma concentration data of 140 children were collected.The population pharmacokinetic model of cefoperazone in the pediatric population was established by nonlinear mixed effects model method,and the predictive performance of the final model was verified by goodness-of-fit,visual predictive check(VPC),and normal predictive distribution error(NPDE).Simulation tests were used to evaluate the rationality of different medication regimens.Results:The final model evaluation results showed that the model was stable and the prediction results were reliable,and the obtained pharmacokinetic parameters of cefoperazone were as follows:Against e.coli:neonate,30 mg·kg^-1,qid,2 h;pediatric patients(one month old-two years old),20 mg·kg^-1,qid,2 h;pediatric patients(two-fourteen years old),10 mg·kg^-1,tid,2 h.Against Klebsiella pneumoniae:neonate,10 mg·kg^-1,tid,2 h;pediatric patients(one month old-two years old),10 mg·kg^-1,tid,2 h;pediatric patients(two-fourteen years old),10 mg·kg^-1,bid,2 h.CONCLUSION The pharmacokinetic model of cefoperazone in pediatric patients was successfully established,and the optimal administration regimen for large intestine and Klebsiella pneumoniae in children of different ages was derived.