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.

项目概要/摘要 这个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 在专家的指导下，韦斯利·M·杰克逊博士能够发展成为一名独立调查员和未来 新生儿学领域的领导者。缺氧缺血性脑病（HIE）是一种常见且往往致命的疾病 在婴儿中。尽管 HIE 婴儿的死亡率或严重神经发育障碍仍然很高 低温治疗的广泛应用。因此，存在着紧迫的、未得到满足的公共卫生需求： 开发辅助疗法以改善该人群的神经发育结果。咖啡因已 经证明可减少 HIE 动物模型的脑损伤，并可能为患有 HIE 的婴儿提供神经保护。 然而，咖啡因尚未在人类 HIE 和治疗性低温治疗中进行研究。博士。 Jackson 提议开发咖啡因的群体药代动力学 (PK) 模型 治疗性低温来表征低温对咖啡因处置的影响 (AIM 1)。他会 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，验证最佳剂量方案 HIE 的低温治疗 (AIM 3)。杰克逊博士制定了一项多学科职业发展计划 培养临床药理学、群体 PK 建模和试验操作方面的技能。的组合 该提案的目标提供的结构化和严格的课程作业以及实践培训将使博士能够 杰克逊培养成为该领域的独立研究员和领导者所需的技能 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位经验丰富的人 具有临床药理学、试验操作和药物开发方面专业知识的指导团队。之上 成功完成拟议的以患者为导向的研究职业发展奖，博士。 杰克逊将获得必要的先进 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，他还将建立一个平台，系统地 在可能改变的程序或疾病状态的背景下评估危重婴儿的治疗 药物 PK，从而促进这一弱势群体的药物开发。