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

青少年饮食失调阿片类药物拮抗药效生物标志物的开发

• 批准号: 10662801
• 负责人: Stephani L Stancil
• 金额: $ 18.75万
• 依托单位: CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662801
• 关键词: Active Learning; Address; Adolescence; Adolescent; Adult; Affect; Anorexia Nervosa; Anterior; Award; Binge Eating; Binge eating disorder; Biological Markers; Brain; Bulimia; Cardiac; Central Nervous System Agents; Child; Childhood; Clinical; Clinical Pharmacology; Clinical Sciences; Clinical Trials; Cross-Over Studies; Cross-Over Trials; Data; Development; Development Plans; Dorsal; Dose; Drug Design; Drug Exposure; Drug Kinetics; Eating Behavior; Eating Disorders; Environment; Enzymes; Food; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genetic Variation; Goals; Hour; Individual; Intervention; Joints; K-Series Research Career Programs; Link; Malnutrition; Medical center; Mental Health; Mental disorders; Mentors; Modeling; Morbidity - disease rate; Naltrexone; National Institute of Mental Health; Neuropharmacology; Obesity; Opioid; Opioid Antagonist; Opioid Receptor; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Placebo Control; Plasma; Play; Positioning Attribute; Precision therapeutics; Randomized; Randomized, Controlled Trials; Recommendation; Research Institute; Research Personnel; Rewards; Risk; Role; Sampling; Site; Structure; Substance Use Disorder; System; Taste Perception; Teenagers; Therapeutic; Training; Translational Research; Visualization; Vomiting; Vulnerable Populations; aged; alternative treatment; antagonist; binge type behavior; biomarker development; biomarker validation; brain reward regions; career; career development; cingulate cortex; craving; design; drug action; drug development; drug discovery; drug repurposing; efficacy trial; frontier; imaging facilities; interest; male; medical schools; model development; mortality; neuroimaging; neuroimaging marker; neuropsychopharmacology; pediatric department; pharmacodynamic biomarker; pharmacologic; pleasure; practical application; psychopharmacologic; purge; purging behavior; randomized, clinical trials; research and development; response; response biomarker; skill acquisition; substance use; translational scientist

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.

项目概要 这项为期 4 年的 K23 提案的总体目标是支持 Stephani Stancil 博士成为一名独立的 药效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，特别是饮食失调疗法。 与 NIMH 的优先顺序和国家心理健康咨询委员会工作组保持一致 定量药理学早期试验的建议，特别是在弱势群体中。 饮食失调 (ED)，包括神经性贪食症、神经性厌食症-暴食/通便和暴食症， 以暴食和净化行为（例如呕吐）为特征，通常开始于青春期，并且 影响高达 5% 的青少年，ED 与严重的发病率有关（例如营养不良、心脏功能不全、 物质使用障碍的发展），在所有精神疾病中死亡率最高，并且不属于 该职业发展提案将利用 Stancil 博士的临床经验。 药物暴露查询方面的药理学专业知识并将她的职业重点扩展到临床 神经精神药理学使她能够定义儿童和中枢神经系统药物的作用 综合职业发展计划 (CDP) 包含三个培训目标：1) 神经影像学，2）儿科随机临床试验，3）暴露反应模型，以过渡博士。 通过 CDP 的结构化指导、教学培训和培训，将 Stancil 培养成一名成功的独立调查员。 体验式学习将应用于一项针对青少年的随机、安慰剂对照交叉试验 狂欢/清除 ED 以实现以下目标： 目标 1) 确定神经影像学的敏感性 通过阿片类药物拮抗作用奖励系统调节的生物标志物，目标 2) 开发暴露-反应模型 对于纳曲酮，Stancil 博士的职业发展和研究将在非常有利和良好的情况下进行。 合适的环境，包括三级学术儿童医学中心、儿童研究所、 两所地区医学院共用儿科、一个优秀的影像中心和 完成该项目后，Stancil 博士将推进药效学领域的发展。 儿科心理健康生物标志物开发并生成数据以支持 R01 应用程序 确定所提出的药效生物标志物的有效性，她将有能力成为一名药物治疗师。 药效生物标志物开发和暴露-反应联动降低风险领域的领导者 早期药物开发并促进儿科精准治疗方法 神经精神药理学。

项目成果

Pharmacogenetics and Oxcarbazepine in Children and Adolescents: Beyond HLA-B*15:02.

儿童和青少年的药物遗传学和奥卡西平：超越 HLA-B*15:02。

• DOI: 10.1089/cap.2023.0064
• 发表时间: 2024-02-01
• 期刊: Journal of child and adolescent psychopharmacology
• 影响因子: 1.9
• 作者: Stephani L. Stancil;Tracy S;ritter;ritter;J. Strawn
• 通讯作者: J. Strawn

Potential biomarker of brain response to opioid antagonism in adolescents with eating disorders: a pilot study.

饮食失调青少年大脑对阿片类药物拮抗反应的潜在生物标志物：一项试点研究。

• 发表时间: 2023
• 作者: Stancil, Stephani L;Yeh, Hung;Brucks, Morgan G;Bruce, Amanda S;Voss, Michaela;Abdel;Brooks, William M;Martin, Laura E
• 通讯作者: Martin, Laura E