Dose Optimization for Novel Drugs for Infants with Hypoxic-Ischemic Encephalopathy

项目摘要/摘要 这项以患者为导向的导师研究职业发展奖将提供一个有条理的环境 在专家的指导下，使韦斯利·M·杰克逊博士能够发展成为一名独立的研究员和未来 新生儿科领域的领先者。摘要缺氧缺血性脑病(HIE)是一种常见且往往致命的疾病。 在婴儿身上。HIE婴儿的死亡率或严重神经发育障碍仍然很高，尽管 广泛使用治疗性低温疗法。因此，有一种迫切的、未得到满足的公共卫生需求 开发辅助疗法以改善这一人群的神经发育结果。咖啡因一直是 可减少HIE动物模型的脑损伤，并可能为HIE婴儿提供神经保护。 然而，咖啡因在人类缺氧缺血性脑病和治疗性低温中的作用还没有被研究过。Dr。 杰克逊建议开发一个咖啡因的群体药代动力学(PK)模型，在 治疗性低温以表征低温对咖啡因处置的影响(AIM 1)。他会的 利用剂量模拟来优化咖啡因治疗方案，以达到治疗水平(目标2)。 最后，他将在24名接受咖啡因治疗的婴儿的开放标签试验中验证最佳剂量方案。 治疗性亚低温治疗HIE(AIM 3)。杰克逊博士制定了一项多学科的职业发展计划 培养临床药理学、群体PK建模和试验操作方面的技能。这两种技术的结合 这项提案的目标是提供结构化和严谨的课程以及实践培训，这将使Dr。 杰克逊需要发展必要的技能，成为一名独立的研究人员和该领域的领导者 新生儿科。为了指导他完成这一学术发展，杰克逊博士召集了一位经验丰富的 在临床药理学、试验操作和药物开发方面具有专业知识的导师团队。vt.在.的基础上 圆满完成了拟议的以患者为导向的导师研究职业发展奖，Dr。 杰克逊将获得必要的高级PK和临床试验技能，以追求终身职业生涯 为危重婴儿开发安全有效的药物。此外，他将建立一个平台，系统地 在可能改变的程序或疾病状态的设置中评估危重婴儿的治疗 毒品PK，从而推动这一弱势群体的毒品开发。

Project Summary/Abstract This Mentored Patient-Oriented Research Career Development Award will provide a structured environment with expert mentorship to enable Dr. Wesley M. Jackson to develop as an independent investigator and future leader in the field of neonatology. Hypoxic-ischemic encephalopathy (HIE) is a common and often fatal disease in infants. Mortality or severe neurodevelopmental impairment in infants with HIE remain high, despite the widespread use of therapeutic hypothermia. As a result, there is an urgent, unmet public health need to develop adjuvant therapies to improve neurodevelopmental outcomes in this population. Caffeine has been shown to reduce brain injury in animal models of HIE and may offer neuroprotection in infants with HIE. However, caffeine has not been studied in the setting of HIE and therapeutic hypothermia in humans. Dr. Jackson proposes to develop a population pharmacokinetics (PK) model of caffeine in the setting of therapeutic hypothermia to characterize the effects of hypothermia on caffeine disposition (AIM 1). He will utilize dosing simulations to optimize the caffeine treatment regimen to achieve therapeutic levels (AIM 2). Finally, he will validate the optimal dosing regimen in an open-label trial of caffeine in 24 infants receiving therapeutic hypothermia for HIE (AIM 3). Dr. Jackson developed a multidisciplinary career development plan to develop skills in clinical pharmacology, population PK modeling, and trials operations. The combination of structured and rigorous coursework with practical training provided by the aims of this proposal will allow Dr. Jackson to develop the skills necessary to become an independent researcher and leader in the field of neonatology. To guide him through this academic development, Dr. Jackson has assembled an experienced mentorship team with expertise in clinical pharmacology, trials operations, and drug development. Upon successful completion of the proposed Mentored Patient-Oriented Research Career Development Award, Dr. Jackson will have acquired the necessary advanced PK and clinical trial skills to pursue a lifelong career in developing safe and effective drugs for critically ill infants. Further, he will establish a platform to systematically evaluate therapies for critically ill infants in the setting of procedures or disease states which are likely to alter drug PK, thereby advancing drug development in this vulnerable population.