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

婴儿缺氧缺血性脑病新药的剂量优化

• 批准号: 10643020
• 负责人: Wesley M Jackson
• 金额: $ 17.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643020
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adjuvant Therapy; Age; Animal Model; Apnea; Birth Weight; Blood flow; Brain; Brain Injuries; Caffeine; Cessation of life; Childhood; Clinical Pharmacology; Clinical Trials; Clinical Trials Design; Cohort Studies; Conduct Clinical Trials; Creatinine; Critical Illness; Cytochrome P450; Data; Development; Development Plans; Disease; Dose; Drug Kinetics; Drug usage; Enrollment; Environment; Enzymes; Faculty; Future; Goals; Health; Hospitals; Human; Hypoxia; Infant; Injury; Investigational New Drug Application; Lead; Live Birth; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Neonatology; Neurodevelopmental Impairment; Organ; Outcome; Pharmaceutical Preparations; Phase; Placebo Control; Population; Pre-Clinical Model; Procedures; Public Health; Randomized; Recording of previous events; Regimen; Research; Research Personnel; Resources; Safety; Serum; Site; Structure; Therapeutic; Therapeutic Uses; Training; Treatment Protocols; United States National Institutes of Health; Validation; Vulnerable Populations; Weight; career; career development; design; drug development; drug disposition; experience; improved; improved outcome; methylxanthine; model development; mortality; multidisciplinary; natural hypothermia; neonatal hypoxic-ischemic brain injury; neuroprotection; novel therapeutics; open label; operation; pharmacokinetic model; pilot trial; postnatal; preterm newborn; prevent; prospective; protective effect; research and development; simulation; skills

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.

项目摘要/摘要 这个受到指导的以患者为导向的研究职业发展奖将提供一个结构化的环境 通过专家指导，使韦斯利·M·杰克逊博士能够发展为独立研究者和未来 新生儿学领域的领导者。缺氧 - 缺血性脑病（HIE）是一种常见且通常是致命的疾病 在婴儿中。尽管有 广泛使用治疗性体温过低。结果，紧急，未满足的公共卫生需要 开发辅助疗法以改善该人群的神经发育结果。咖啡因一直是 证明可以减少HIE动物模型的脑损伤，并可能在患有HIE的婴儿中提供神经保护作用。 然而，咖啡因尚未在人类的HIE和治疗性体温过低的情况下进行研究。博士 杰克逊（Jackson）提议开发咖啡因种群药代动力学（PK） 治疗性体温过低以表征体温过低对咖啡因性质的影响（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（AIM 2）。 最后，他将在24名婴儿的咖啡因开放标签试验中验证最佳剂量方案 HIE的治疗性体温过低（AIM 3）。杰克逊博士制定了一个多学科职业发展计划 发展临床药理学，人群PK建模和试验操作的技能。结合 结构化和严格的课程以及该提案目的提供的实践培训将允许博士 杰克逊（Jackson）发展成为一名独立研究人员和领导者所必需的技能 新生儿学。为了指导他完成这一学术发展，杰克逊博士召集了一个经验丰富的 具有临床药理学，试验操作和药物开发专业知识的指导团队。之上 成功完成了拟议的指导的注重患者的研究职业发展奖，博士 杰克逊将获得必要的高级PK和临床试验技巧，从事终身职业 为重症婴儿开发安全有效的药物。此外，他将建立一个系统的平台 在可能改变的程序或疾病状态下评估重症婴儿的疗法 药物PK，从而在这一脆弱人群中推进了药物开发。