Department of Pediatrics, Stanford University, Palo Alto, California 94304, USA.
Pharmacotherapy. 2013 Jul;33(7):718-26. doi: 10.1002/phar.1263. Epub 2013 Apr 1.
To evaluate the pharmacokinetics of gentamicin in neonates with hypoxic ischemic encephalopathy (HIE) receiving hypothermia and to identify an empiric gentamicin dosing strategy in this population that optimizes achievement of target peak and trough concentrations.
Population pharmacokinetic study using retrospective medical record data.
Tertiary neonatal intensive care unit.
A total of 29 full-term neonates diagnosed with HIE treated with hypothermia who received gentamicin and underwent therapeutic drug monitoring
Patient demographics and gentamicin concentration data were retrospectively collected over a 2-year period. A population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). Using the developed model, Monte Carlo simulations were performed to evaluate the probability of achieving target peak (> 6 mg/L) and trough (< 2 mg/L) gentamicin concentrations for various potential dosing regimens. A one-compartment model best described the available gentamicin concentration data. Birthweight and serum creatinine significantly influenced gentamicin clearance. For the typical study neonate (birthweight 3.3 kg, serum creatinine 0.9 mg/dl), clearance was 0.034 L/hour/kg and volume was 0.52 L/kg. At a 24-hour dosing interval, Monte Carlo simulations predicted target gentamicin peak and trough concentrations could not be reliably achieved at any dose. At a 36-hour dosing interval, a dose of 4-5 mg/kg is predicted to achieve target gentamicin peak and trough concentrations in more than 90% of neonates.
Gentamicin clearance is decreased in neonates with HIE treated with hypothermia compared with previous reports in nonasphyxiated normothermic full-term neonates. A prolonged 36-hour dosing interval will be needed to achieve target gentamicin trough concentrations in this population. Further prospective evaluation of this dosing recommendation is needed.
评估接受低温治疗的患有缺氧缺血性脑病（HIE）的新生儿体内庆大霉素的药代动力学，并确定在该人群中优化实现目标峰和谷浓度的经验性庆大霉素给药策略。
使用回顾性病历数据进行群体药代动力学研究。
三级新生儿重症监护病房。
共 29 例足月诊断为 HIE 并接受低温治疗的新生儿，接受庆大霉素治疗并进行治疗药物监测。
在 2 年期间回顾性收集患者人口统计学数据和庆大霉素浓度数据。使用非线性混合效应模型（NONMEM）开发基于人群的药代动力学模型。使用开发的模型进行蒙特卡罗模拟，以评估各种潜在给药方案实现目标峰（>6mg/L）和谷（<2mg/L）庆大霉素浓度的概率。一个单室模型最好地描述了可用的庆大霉素浓度数据。出生体重和血清肌酐显著影响庆大霉素清除率。对于典型的研究新生儿（出生体重 3.3kg，血清肌酐 0.9mg/dl），清除率为 0.034L/h/kg，体积为 0.52L/kg。在 24 小时给药间隔，蒙特卡罗模拟预测任何剂量都不能可靠地达到目标庆大霉素峰和谷浓度。在 36 小时给药间隔，预测剂量为 4-5mg/kg 可使超过 90%的新生儿达到目标庆大霉素峰和谷浓度。
与非窒息性正常体温足月新生儿的先前报告相比，接受低温治疗的患有 HIE 的新生儿的庆大霉素清除率降低。需要延长 36 小时的给药间隔才能在该人群中达到目标庆大霉素谷浓度。需要进一步前瞻性评估这种给药建议。
