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咖啡因在患有缺氧缺血脑病的婴儿群体的药理动力学:一期I期,剂量升级试验
Elizabeth J Thompson1,2,3, Daniel Gonzalez1, Julie Dumond2
1Duke Clinical Research Institute, Durham, NC, USA.
Journal of clinical pharmacology
|February 12, 2025
概括
冷却是低氧性缺血性脑病变 (HIE) 的标准. 咖啡因可能会增强神经保护,但对于接受冷却的HIE婴儿的当前剂量需要调整,以获得最佳的治疗暴露.
科学领域:
- 新生儿药理学 新生儿药理学
- 神经临界护理是指神经临界护理.
背景情况:
- 低毒性缺血性脑病变 (HIE) 是新生儿死亡率和发病率的主要原因之一.
- 治疗性低温是HIE的标准治疗方法.
- 咖啡因具有抗炎和抗氧化性质,这表明咖啡因作为辅助疗法的潜在神经保护作用.
研究的目的:
- 在接受治疗冷却的HIE期满婴儿中,对静脉注射咖啡因的群体药理动力学进行表征.
- 评估冷却和其他共变量对咖啡因药理动学的影响.
- 模拟不同的剂量方案,以评估达到度的度目标.
主要方法:
- 第1阶段,剂量升级研究设计.
- 静脉注射咖啡因:最初的20毫克/千克的加重剂量,然后是5或10毫克/千克的维持剂量.
- 使用NONMEM (v7.5) 进行的人口药理动力学分析.
- 共变量分析,以评估临床因素 (包括冷却) 对药物动力学参数的影响.
- 用剂量模拟来预测血暴露水平.
主要成果:
- 一个单间模型充分描述了咖啡因的药理动力学.
- 总体清除值为0.445 L/h/70 kg,分布量为87.1 L/70 kg.
- 当前剂量 (20 mg/kg,其次是5 mg/kg) 导致89.5%的模拟暴露低于目标范围 (15-25 mg/L).
- 模拟的30毫克/公斤,其次是5或10毫克/公斤的治疗方案预测了>50%的婴儿达到目标暴露,在毒性范围 (>46毫克/升) 中<20%.
- 与没有HIE或冷却的早产婴儿相比,患有HIE的期满婴儿显示出类似的体重正常化清除,但体重正常化分布体积较高.
结论:
- 在经过冷却的HIE期满婴儿中,体重正常化咖啡因清除与早产婴儿相似,但分布体积更大.
- 目前的咖啡因剂量方案不足以达到婴儿治疗度,HIE接受冷却.
- 替代剂量策略,如更高的负载或维持剂量,在未来的临床试验中进行研究以优化神经保护.
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