Development of a Pharmacodynamic Biomarker of Opioid Antagonism in Adolescents with Eating Disorders

项目摘要 这项为期4年的K23提案的总体目标是支持Stephani Stanford博士成为一名独立的 药效学生物标志物开发领域的研究者，以支持定量早期药物 儿科神经精神药理学的发展，特别是进食障碍治疗。这项建议 与NIMH的优先级和国家心理健康咨询理事会的优先级保持一致 建议进行定量药理学早期试验，特别是在脆弱人群中。 进食障碍（艾德），包括神经性贪食症、神经性厌食症-暴食症和暴食症， 以暴饮暴食和排泄行为为特征（例如，呕吐），通常开始于青春期， 影响了5%的青少年ED与显著的发病率相关（例如，营养不良心脏受损 药物使用障碍的发展），有任何精神疾病的死亡率最高， 对目前的药物治疗有反应。这份职业发展计划将利用斯坦利博士的临床经验， 药物暴露调查的药理学专业知识，并将其职业重点扩展到临床 神经精神药理学，使她能够定义儿童中枢神经系统药物作用， 青少年。全面的职业发展计划包含三个培训目标： 神经影像学，2）儿科随机临床试验，和3）疗效反应模型，以过渡博士。 把他变成一个成功的独立调查员。CDP的结构化指导、教学培训和 经验学习将应用于一项在青少年中进行的随机、安慰剂对照交叉试验， 放纵/放纵艾德以实现以下目标：目标1）确定神经成像的灵敏度 通过阿片拮抗作用调节奖赏系统的生物标志物，目的2）开发暴露-反应模型 纳洛酮Stanford博士的职业发展和研究将在一个非常有利和良好的- 适合的环境，包括第三学术儿童医疗中心，儿童研究所， 由两所地区医学院共享的联合儿科，一个杰出的成像中心和 边境CTSA。完成这个项目后，Stanford博士将推进药效学领域 儿科心理健康生物标志物的开发，并生成数据以支持R01应用， 确定拟定药效学生物标志物的有效性。她将有能力成为 在药效学生物标志物开发和消除风险的确定-反应联系领域的领导者 早期药物开发，并促进儿童的精确治疗方法 神经精神药理学

Project Summary The overall goal of this 4-year K23 proposal is to support Dr. Stephani Stancil to become an independent investigator in the field of pharmacodynamic biomarker development to support quantitative early-stage drug development in pediatric neuropsychopharmacology, specifically eating disorder therapeutics. This proposal aligns with NIMH’s prioritization of and the National Advisory Mental Health Council workgroup recommendations for quantitative pharmacologic early-stage trials, particularly in vulnerable populations. Eating disorders (ED), including Bulimia Nervosa, Anorexia Nervosa-Binge/Purge and Binge Eating Disorder, are characterized by binge eating and purge behaviors (e.g., vomiting), typically begin in adolescence, and affect up to 5% of teens. EDs are associated with significant morbidity (e.g., malnutrition, cardiac compromise, development of substance use disorder), have the highest mortality rate of any psychiatric illness and are not responsive to current pharmacotherapy. This career development proposal will leverage Dr. Stancil’s clinical pharmacology expertise in drug exposure inquiry and expand her career focus to clinical neuropsychopharmacology to enable her to define central nervous system drug action in children and adolescents. The comprehensive career development plan (CDP) contains three training objectives: 1) neuroimaging, 2) pediatric randomized clinical trials, and 3) exposure-response modeling, to transition Dr. Stancil into a successful, independent investigator. The CDP’s structured mentoring, didactic training and experiential learning will be applied to a randomized, placebo-controlled crossover trial in adolescents with Binge/Purge ED to accomplish the following aims: Aim 1) Determine the sensitivity of a neuroimaging biomarker to reward system modulation by opioid antagonism, Aim 2) Develop an Exposure-Response Model for naltrexone. Dr. Stancil’s career development and research will take place in a highly favorable and well- suited environment that includes a tertiary academic children’s medical center, children’s research institute, joint department of pediatrics shared by two regional medical schools, an outstanding imaging center and the Frontiers CTSA. After completing this project, Dr, Stancil will have advanced the field of pharmacodynamic biomarker development in pediatric mental health and generated data to support an R01 application to establish the validity of the proposed pharmacodynamic biomarker. She will be well-positioned to become a leader in the field of pharmacodynamic biomarker development and exposure-response linkage to de-risk early-stage drug development and facilitate a precision therapeutics approach to pediatric neuropsychopharmacology.