A comprehensive approach to understanding the determinants of metformin pharmacokinetics and pharmacodynamics in youth with type 2 diabetes

项目总结 年轻人中2型糖尿病(T2D)的患病率正在上升，目前的管理策略无效 在维持血糖控制的持久性方面。二甲双胍是治疗青年T2D的基石，但 患有T2D的青年二甲双胍治疗失败率较高。治疗失败的原因 仍然未知，需要全面了解才能优化给药策略 安全且经济实惠的治疗。为了解决这一未得到满足的医疗需求，Shylaja Serinivesan MD提议建立 关于她成功的以病人为导向的基因研究通过这个职业发展奖与整体 目的用综合方法了解青年糖尿病患者二甲双胍疗效的影响因素。 T2D。在多学科指导团队的协助下，她将评估药物的药理学、临床 以及患有T2D的青年患者二甲双胍反应的生理决定因素。斯里尼瓦桑博士提出了以下建议 目的：(1)建立一个群体PK模型来描述二甲双胍在青壮年的药代动力学 T2D；(2)表征二甲双胍长期疗效的变化，结合综合临床， 药理学和遗传学数据与青少年T2D疾病进展的关系并开发出临床可用的 精确给药工具；以及(3)在青年T2D的先导性研究中评价二甲双胍的精确给药工具 在真实的临床环境中。为了推进这些研究，她可以访问来自 儿童T2D患者。在目标1中，斯里尼瓦桑博士将使用60%的PK数据开发一个人口PK模型 从加州大学旧金山分校招募的患有T2D的青年。在目标2中，她将开发一个纵向模型来描述 剂量、预计二甲双胍PK(目标1)、临床因素、遗传因素(如果有)与 使用已经从699名患有T2D的青年中收集的样本进行二甲双胍的反应 青少年中的2型糖尿病(今天)研究。然后，她将利用这些结果开发出一种 临床可用的精密给药工具。在目标3中，她将在一项20人的初步研究中评估这种精确的剂量工具 来自加州大学旧金山分校的Young，在真实的临床环境中比较了精确剂量和常规剂量的二甲双胍。 这项提案的结果将通知R01，其中将测试二甲双胍的精确剂量算法 在一项大型随机对照试验中，并将扩大到包括其他药物类别。斯里尼瓦桑博士的长- 任期的职业目标是成为一名独立的临床研究人员，并利用药理学和遗传学 方法改进青少年T2D的治疗策略。在这个职业发展奖上，她的训练 目标是获得临床药理学和定量药代动力学方面的经验；精通 先进的生物统计学方法；获得进行儿科临床试验的经验；以及从事 职业发展活动，为R01资金做准备。她将通过这些建议来实现这些目标 并来自世界一流的多学科辅导团队，参与相关教学 课程作业和实践研究经验，这些都是未来独立研究成功所必需的。

PROJECT SUMMARY The prevalence of type 2 diabetes (T2D) is increasing in youth with current management strategies ineffective at maintaining durability of glycemic control. Metformin is the cornerstone of treatment of T2D in youth, yet youth with T2D have high treatment failure rates on metformin therapy. The reasons for treatment failure remain unknown, and need to be comprehensively understood in order to optimize dosing strategies for this safe and cost-effective therapy. To address this unmet medical need, Shylaja Srinivasan MD proposes to build on her successful patient-oriented genetic research through this career development award with the overall objective to use an integrated approach to understand the determinants of metformin response in youth with T2D. With the assistance of a multi-disciplinary mentoring team, she will evaluate the pharmacological, clinical and physiological determinants of metformin response in youth with T2D. Dr. Srinivasan proposes the following aims: (1) develop a population PK model to describe the pharmacokinetics (PK) of metformin in youth with T2D; (2) characterize the variance in long-term response to metformin, integrating comprehensive clinical, pharmacological and genetic data with disease progression in youth with T2D and develop a clinically usable precision dosing tool; and (3) evaluate the precision dosing tool for metformin in a pilot study of youth with T2D in a real clinical setting. To advance these studies, she has access to large datasets and samples from pediatric patients with T2D. In Aim 1, Dr. Srinivasan will develop a population PK model using PK data from 60 youth with T2D recruited from UCSF. In Aim 2, she will develop a longitudinal model to characterize the association between dose, predicted metformin PK (Aim 1), clinical factors, genetic factors if any and metformin response using samples already collected from 699 youth with T2D from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. She will then utilize these results to develop a clinically usable precision dosing tool. In Aim 3, she will evaluate the precision dosing tool in a pilot study of 20 youth from UCSF, comparing precision dosing with conventional dosing for metformin in a real clinical setting. Results from this proposal will inform an R01 in which precision dosing algorithms for metformin will be tested in a large randomized control trial and will be expanded to include other drug classes. Dr. Srinivasan's long- term career goal is to become an independent clinical researcher and to leverage pharmacological and genetic methods to improve therapeutic strategies for youth with T2D. In this career development award, her training goals are to gain experience in clinical pharmacology and quantitative pharmacokinetics; become proficient in advanced biostatistical methods; gain experience in the conduct of pediatric clinical trials; and engage in career development activities in preparation for R01 funding. She will accomplish these goals with the advice and mentoring from a world-class multi-disciplinary mentoring team, participation in relevant didactic coursework and hands-on research experience, all necessary for future independent research success.