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.

项目总结/摘要 这个指导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Wesley M.杰克逊发展为一个独立的调查员和未来 医学领域的领导者。缺氧缺血性脑病（Hypoxic-ischemic encephalopathy，HIE）是一种常见且常致命的疾病 在婴儿身上。新生儿缺氧缺血性脑病的死亡率和严重的神经发育障碍仍然很高， 低温治疗的广泛应用。因此，有一个紧迫的、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。咖啡碱就已 在缺氧缺血性脑病动物模型中显示出减少脑损伤，并可能为缺氧缺血性脑病婴儿提供神经保护。 然而，咖啡因尚未在人类HIE和治疗性体温过低的背景下进行研究。博士 杰克逊建议在以下条件下建立咖啡因的群体药代动力学（PK）模型： 治疗性低温，以表征低温对咖啡因处置的影响（AIM 1）。他将 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名接受咖啡因治疗的婴儿中进行一项开放标签试验， 治疗性低温治疗新生儿缺氧缺血性脑病（AIM 3）。杰克逊博士制定了一个多学科的职业发展计划， 培养临床药理学、群体PK建模和试验操作技能。的组合 结构化和严格的课程与实践培训提供了本建议的目的将允许博士。 杰克逊发展必要的技能，成为一个独立的研究人员和领导者在该领域的 医学。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拥有专业知识的导师团队。后 成功完成拟议的指导病人为导向的研究职业发展奖，博士。 杰克逊将获得必要的先进的PK和临床试验技能，以追求终身职业， 为重症婴儿开发安全有效的药物。此外，他将建立一个平台， 在可能改变的程序或疾病状态下评估危重婴儿的治疗方法 药物PK，从而促进这一脆弱人群的药物开发。