拉氧头孢对映异构体在儿童群体中的药动学研究和剂量优化

目的:建立拉氧头孢对映异构体在儿童患者中的群体药动学模型,研究拉氧头孢在儿童患者体内的药动学特点,为拉氧头孢在儿童患者中的个体化用药提供依据。方法:检测145例静脉滴注拉氧头孢患儿的血药浓度,收集患儿临床资料。采用非线性混合效应模型法建立拉氧头孢对映异构体在儿童患者群体中药动学模型,并用自举法、拟合优度图和正态化预测分布误差进行验证。采用蒙特卡洛模拟评价不同给药方案的合理性。结果:四房室模型可以较好描述拉氧头孢对映异构体在儿童患者体内的药动学特征。最终模型稳定,预测结果可靠。拉氧头孢R和S对映异构体的表观分布容积(V_d)分别为5.57 L和4.15 L,清除率(CL)分别为0.78 L·h^-1和1.32 L·h^-1。体质量对拉氧头孢异构体药动学参数有显著影响。结论:该研究成功建立了拉氧头孢对映异构体在儿童患者群体中的药动学模型,可为拉氧头孢的个体化用药提供参考。

Population pharmacokinetics and dose optimization of latamoxef epimers in pediatric patients

OBJECTIVE To establish a population pharmacokinetic model of latamoxef epimers in pediatric patients,and to study the pharmacokinetic characteristics of latamoxef in pediatric patients so as to provide a basis for individualized dosing of latamoxef in children.METHODS Blood concentrations were collected from 145 pediatric patients after intravenous administration of latamoxef and their clinical data were recorded in detail.The pharmacokinetic model of latamoxef epimers was constructed by using non-linear mixed-effects method in pediatric patients.Bootstrap method,goodness-of-fit plots and normalized predicted distribution errors were utilized to evaluate the stability and fitness of the model.Monte Carlo simulations were used to evaluate the rationality of different dosing regimens.RESULTS The characteristics of population pharmacokinetics for latamoxef epimers were best described by a four-compartment model in pediatric patients.The final model was stable and the prediction results were reliable.The apparent volumes of distribution(V_d) of R- and S-epimer of latamoxef were 5.57 L and 4.15 L,and the clearance(CL) were 0.78 L·h^-1 and 1.32 L·h^-1,respectively.Body weight had a significant effect on the pharmacokinetic parameters of latamoxef epimers.CONCLUSION This study successfully established a population pharmacokinetic model of latamoxef epimers in pediatric patients,which can provide a reference for the individualized dosing of latamoxef in children.