Le Jennifer, Vaida Florin, Nguyen Emily, Adler-Shohet Felice C, Romanowski Gale, Kim Jiah, Vo Tiana, Capparelli Edmund V
University of California San Diego, La Jolla, CA ; Miller Children's Hospital, Long Beach, CA.
University of California San Diego, La Jolla, CA.
J Pharmacol Clin Toxicol. 2014;2(1):1017-1026.
Vancomycin dosing to achieve the area-under-the-curve to minimum inhibitory concentration (AUC/MIC) target of ≥ 400 in children with renal insufficiency is unknown. Our objectives were to compare vancomycin clearance (CL) and initial dosing in children with normal and impaired renal function.
Using a matched case-control study in subjects ≥ 3 months old who received vancomycin ≥ 48 hr, we performed population-based modeling with empiric Bayesian post-hoc individual parameter estimations and Monte Carlo simulations. Cases, defined by baseline serum creatinine (SCr) ≥ 0.9 mg/dL, were matched 1:1 to controls by age and weight.
Analysis included 63 matched pairs with 319 serum concentrations. Mean age (± SD) was 13 ± 6 yr and weight, 51 ± 25 kg. Mean baseline SCr was 0.6 ± 0.2 mg/dL for controls, and 1.3 ± 0.5 for cases. Age, SCr, and weight were independent covariates for CL. Final model parameters and inter-subject variability (ISV) were: CL(L/hr) = 0.235Weight(0.64/SCr)*(ln(DOL)/8.6) ISV=39%, where DOL is day of life. Target AUC/MIC ≥ 400 was achieved in 80% of cases at vancomycin 45 mg/kg/day, but required 60 mg/kg/day for controls. Drug CL improved in 87% of cases due to recovery of renal function.
Due to reduced CL, a less frequent dosing at 15 mg/kg every 8 hr (i.e., 45 mg/kg/day) may be appropriate for some children with renal impairment. Close monitoring of renal function and drug concentrations is prudent to ensure adequate drug exposure, especially in those with renal impairment since recovery of renal function may occur during therapy.
在肾功能不全儿童中，万古霉素给药以达到曲线下面积与最低抑菌浓度（AUC/MIC）≥400的目标尚不清楚。我们的目的是比较肾功能正常和受损儿童的万古霉素清除率（CL）及初始给药剂量。
在接受万古霉素≥48小时的≥3个月大的受试者中进行配对病例对照研究，我们采用基于群体的建模方法并进行经验贝叶斯事后个体参数估计和蒙特卡洛模拟。以基线血清肌酐（SCr）≥0.9mg/dL定义的病例，按年龄和体重与对照1:1配对。
分析包括63对匹配对及319个血清浓度数据。平均年龄（±标准差）为13±6岁，体重为51±25kg。对照组平均基线SCr为0.6±0.2mg/dL，病例组为1.3±0.5mg/dL。年龄、SCr和体重是CL的独立协变量。最终模型参数和个体间变异性（ISV）为：CL（L/hr）=0.235×体重×（0.64/SCr）×（ln（日龄）/8.6），ISV = 39%，其中日龄为出生天数。在万古霉素剂量为45mg/kg/天时，80%的病例达到目标AUC/MIC≥400，但对照组需要60mg/kg/天。由于肾功能恢复，87%的病例药物CL有所改善。
由于CL降低，对于一些肾功能受损儿童，每8小时15mg/kg（即45mg/kg/天）的给药频率可能是合适的。谨慎密切监测肾功能和药物浓度以确保足够的药物暴露，特别是在肾功能受损者中由于治疗期间可能出现肾功能恢复。
