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

项目摘要 2型糖尿病（T2 D）的患病率在年轻人中不断增加，目前的管理策略无效 维持血糖控制的持久性。Metabolic是治疗青年T2 D的基石，但 患有T2 D的青少年在二甲双胍治疗中具有较高的治疗失败率。治疗失败的原因 仍然是未知的，需要全面了解，以优化给药策略， 安全和经济有效的治疗。为了解决这一未满足的医疗需求，Shylaja Srinivasan医学博士建议建立 她成功的病人为导向的遗传研究，通过这个职业发展奖与整体 目的采用综合方法了解青年二甲双胍应答的决定因素， 2型糖尿病在多学科指导团队的协助下，她将评估药理学、临床 和二甲双胍在青年T2 D患者中反应的生理决定因素。斯里尼瓦桑博士提出以下建议 目的：（1）建立一个群体药代动力学模型，以描述二甲双胍在青少年中的药代动力学（PK）， 2型糖尿病;（2）描述二甲双胍长期反应的差异，结合全面的临床， 药物和遗传学数据与青年T2 D患者疾病进展相关，并开发临床可用的 精确给药工具;和（3）在青年T2 D患者的初步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，她可以访问来自世界各地的大型数据集和样本。 2型糖尿病儿科患者。在目标1中，Dr. Srinivasan将使用60名受试者的PK数据开发群体PK模型。 从加州大学旧金山分校招募的T2 D青年。在目标2中，她将开发一个纵向模型来描述 剂量、预测的二甲双胍PK（目标1）、临床因素、遗传因素（如果有）之间的相关性 二甲双胍反应，使用已从治疗选项中的699例T2 D青年患者中采集的样本， 2型糖尿病在青少年和青年（今天）的研究。然后，她将利用这些结果开发一个 临床上可用的精确剂量工具。在目标3中，她将在一项20人的试点研究中评估精确给药工具。 来自加州大学旧金山分校的年轻人，在真实的临床环境中比较二甲双胍的精确剂量与常规剂量。 该提案的结果将告知R 01，其中将测试二甲双胍的精密度给药算法 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。斯里尼瓦桑医生很久- 长期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 改善青年T2 D治疗策略的方法。在这次职业发展奖中，她的培训 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 先进的生物统计方法;获得儿科临床试验的经验;并从事 职业发展活动，为R 01供资做准备。她将通过以下建议实现这些目标 并从一个世界级的多学科指导团队的指导，参与相关的教学 课程和实践研究经验，所有必要的未来独立研究的成功。

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.