Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093-0714, USA.
Pediatr Infect Dis J. 2013 Apr;32(4):e155-63. doi: 10.1097/INF.0b013e318286378e.
: Our objectives were to (1) determine the pharmacokinetic indices of vancomycin in pediatric patients; and (2) compare attainment of 2 target exposures: area under curve (AUC) / minimum inhibitory concentration (MIC) ≥400 and trough concentration ≥15 mcg/mL.
: The population-based pharmacokinetic modeling was performed using NONMEM 7.2 for children ≥3 months old who received vancomycin for ≥48 hours from 2003 to 2011. A 1-compartment model with first-order kinetics was used to estimate clearance, volume of distribution and 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 2.2-13.4) years, weight 22.7 (12.6-46) kg and baseline serum creatinine 0.40 (0.30-0.60) mg/dL. Final model pharmacokinetic indices were clearance (L/h) = 0.248 * Wt * (0.48/serum creatinine) * (ln(age)/7.8) and volume of distribution (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.
我们的目的是：（1）确定儿童患者万古霉素的药代动力学指标；（2）比较达到 2 个目标暴露量：曲线下面积（AUC）/最小抑菌浓度（MIC）≥400 和谷浓度≥15 mcg/mL。
采用 NONMEM 7.2 对 2003 年至 2011 年间接受万古霉素治疗≥48 小时的≥3 个月大的儿童进行基于人群的药代动力学建模。使用 1 房室模型和一级动力学来估计清除率、分布容积和 AUC。进行经验贝叶斯后个体参数和蒙特卡罗模拟（N=11000）。
分析包括 702 例患者，共 1660 个万古霉素血清浓度。中位年龄为 6.6（四分位间距 2.2-13.4）岁，体重 22.7（12.6-46）kg，基线血清肌酐 0.40（0.30-0.60）mg/dL。最终模型药代动力学指标为清除率（L/h）=0.248Wt（0.48/血清肌酐）（ln（年龄）/7.8）和分布容积（L）=0.636Wt。使用这些参数和观察到的 MIC 分布，蒙特卡罗模拟表明，大多数患者的初始中位数剂量 44（39-52）mg/kg/天是不足的。对于≥12 岁的患者给予 60mg/kg/天，对于<12 岁的患者给予 70mg/kg/天的方案，大约 75%的虚拟患者达到目标 AUC/MIC，大约 45%的患者谷浓度≥15。AUC/MIC400 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 作为靶向暴露量是儿童更现实的目标。根据年龄、血清肌酐和 MIC 分布，需要给予 60 至 70mg/kg/天的万古霉素剂量，才能使 75%的患者达到 AUC/MIC≥400。
