Improved vancomycin dosing in children using area under the curve exposure.
Improved vancomycin dosing in children using area under the curve exposure.
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DOI：
10.1097/inf.0b013e318286378e
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发表时间：
2013-04
期刊：
影响因子：
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通讯作者：
Capparelli EV
中科院分区：
文献类型：
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作者：
Le J;Bradley JS;Murray W;Romanowski GL;Tran TT;Nguyen N;Cho S;Natale S;Bui I;Tran TM;Capparelli EV
我们的目标是：（1）确定万古霉素在儿科患者中的药代动力学[PK]指数； (2) 比较两个目标暴露的实现情况：AUC/MIC ≥ 400 和谷浓度 ≥ 15 mcg/mL。使用 NONMEM 7.2 对 2003 年至 2011 年接受万古霉素 ≥ 48 小时的 3 月龄以上儿童进行基于人群的 PK 建模。使用具有一级动力学的单室模型来估计清除率 (CL)、分布体积 (Vd) 和曲线下面积 (AUC)。进行了经验贝叶斯事后个体参数和蒙特卡罗模拟（N=11,000）。分析包括 702 名患者，血清浓度为 1660 万古霉素。中位年龄为 6.6（四分位距 [IQR] 2.2–13.4）岁，体重 22.7 (12.6–46) kg，基线血清肌酐 (SCr) 0.40 (0.30–0.60) mg/dL。最终模型PK指数为：CL(L/h) = 0.248*Wt0.75*(0.48/SCr)0.361*(ln(age)/7.8)0.995； Vd(L) = 0.636*重量。使用这些参数和观察到的 MIC 分布，蒙特卡罗模拟表明，44 (39-52) mg/kg/天的初始中位剂量对于大多数受试者来说是不够的。 ≥ 12 岁受试者的治疗方案为 60 mg/kg/天，< 12 岁受试者的治疗方案为 70 mg/kg/天，约 75% 的虚拟受试者达到目标 AUC/MIC，约 45% 的虚拟受试者达到谷浓度≥ 15。 AUC/MIC ~ 400 对应于谷浓度 ~ 8 至 9 mcg/mL。与谷浓度相比，使用万古霉素 AUC/MIC 进行靶向暴露对于儿童来说是一个更现实的目标。根据年龄、血清肌酐和 MIC 分布，万古霉素剂量为 60 至 70 mg/kg/天，才能使 75% 的患者达到 AUC/MIC ≥ 400。
Our objectives were to: (1) determine the pharmacokinetic [PK] indices of vancomycin in pediatric patients; and (2) compare attainment of two target exposures: AUC/MIC ≥ 400 and trough concentration ≥ 15 mcg/mL. The population-based PK modeling was performed using NONMEM 7.2 for children ≥ 3 months old who received vancomycin for ≥ 48 hr from 2003 to 2011. A one-compartment model with first-order kinetics was used to estimate clearance (CL), volume of distribution (Vd) and area-under-curve (AUC). Empiric Bayesian post-hoc individual parameters and Monte Carlo simulations (N=11,000) were performed. Analysis included 702 patients with 1660 vancomycin serum concentrations. Median age was 6.6 (interquartile range [IQR] 2.2–13.4) yr, weight 22.7 (12.6–46) kg, and baseline serum creatinine (SCr) 0.40 (0.30–0.60) mg/dL. Final model PK indices were: CL(L/h) = 0.248*Wt0.75*(0.48/SCr)0.361*(ln(age)/7.8)0.995; and Vd(L) = 0.636*Wt. Using these parameters and the observed MIC distribution, Monte Carlo simulation indicated that the initial median dose of 44 (39–52) mg/kg/day was inadequate in most subjects. Regimens of 60 mg/kg/day for subjects ≥ 12 years old and 70 mg/kg/day for those < 12 years old achieved target AUC/MIC in ~ 75% and trough concentrations ≥ 15 in ~ 45% of virtual subjects. An AUC/MIC ~ 400 corresponded to trough concentration ~ 8 to 9 mcg/mL. Targeted exposure using vancomycin AUC/MIC, compared with trough concentrations, is a more realistic target in children. Depending on age, serum creatinine, and MIC distribution, vancomycin in a dosage of 60 to 70 mg/kg/day was necessary to achieve AUC/MIC ≥ 400 in 75% of patients.