去甲万古霉素成人药动学数据外推至儿童群体和剂量优化

目的：获得去甲万古霉素在儿童群体中的药动学特征，优化给药方案以指导临床个体化用药。方法：将成人去甲万古霉素群体药动学（PPK）模型外推得到儿童模型；通过拟合优度图（goodness-of-fit）、可视化预测检验（VPC）及正态化预测分布误差（NPDE）验证外推模型的稳定性和预测性能。采用贝叶斯法获取个体药动学参数，通过蒙特卡洛模拟法评价和优化给药方案。结果：去甲万古霉素在儿童群体中药动学参数的群体均值分别为总体清除率（CL）0.11 L·kg^-1·h^-1、中央室分布容积（V₁）6.08 L、周边室分布容积（V₂）6.21 L、室间清除率（Q）2.32 L·h^-1。拟合优度、VPC和NPDE结果表明外推模型稳定性和预测性能均较好。蒙特卡洛模拟结果提示对于肾功能正常的患儿，去甲万古霉素用于治疗不同MIC（0.25，0.5，0.75和1 mg·L^-1）细菌感染时，要使体内暴露水平的目标获得概率（PTA）达到90%以上，对葡萄球菌属的理想日剂量应分别为16，32和48 mg·kg^-1及以上，对肠球菌属的理想日剂量应分别为16，24，32和40 mg·kg^-1。结论：本研究成功外推得到去甲万古霉素在儿童群体的药动学模型和参数，模拟结果显示，现行去甲万古霉素给药剂量可能偏低。

Pharmacokinetic characteristics extrapolated from adult's data and dosing optimization of norvancomycin in children population

OBJECTIVE To study the pharmacokinetic characteristics of norvancomycin in children and to optimize the dosage regimen, thus guiding clinical individualized medication. METHODS The population pharmacokinetic (PPK) model of norvancomycin in adults was extrapolated to produce a pediatric model. The stability and prediction of the extrapolated pharmacokinetic model were evaluated by goodness-of-fit, visual predictive check (VPC), normalized predictive distribution error (NPDE). The individualized pharmacokinetic parameters were obtained by Bayesian method. Optimized dosage regimens were evaluated and optimized by Monte Carlo simulation. RESULTS The population mean values of pharmacokinetic parameters of norvancomycin in children were as follows:drug clearance (CL) 0.11 L·kg^-1·h^-1, central compartment distribution volume (V₁) 6.08L, peripheral compartment distribution volume (V₂) 6.21L, and inter-compartmental clearance (Q) 2.32 L·h^-1. The goodness-of-fit, VPC, and NPDE results indicated that the stability and prediction performance of the extrapolated model were fairly good. Monte Carlo simulation results suggested that for children with normal renal function, when norvancomycin is used to treat bacterial infections with different MICs (0.25, 0.5, 0.75 and 1 mg · L-1), probabilities of target attainment of in vivo exposure level should reach more than 90%, the ideal daily dose for Staphylococcus should be 16, 32 and 48 mg·kg^-1 and above, respectively, and the ideal daily dose for Enterococcus should be 16, 24, 32 and 40 mg·kg^-1, respectively. CONCLUSION The extrapolated PPK model of norvancomycin in pediatric patients was established successfully, and simulation results suggested that the current dosage regimens of norvancomycin may be relatively low.