Optimizing Vancomycin Therapy in Children

项目总结/摘要 K23职业发展奖的候选人Kevin J. Downes博士是一位儿科传染病专家， 儿科临床药理学培训和临床研究背景的专家，重点是 抗菌药物药代动力学/药效学（PK/PD）和药物相关急性肾损伤 （阿基）。唐斯博士的长期职业目标是成为一名独立的调查员， 药物计量学和临床试验。拟议的指导研究和职业发展计划将促进 通过促进唐斯博士的短期目标，以获得教学和经验培训， 参数和非参数群体PK建模和模拟、贝叶斯自适应控制和临床 试验设计他组建了一个强大的导师团队，由Athena Zuppa MD，MSCE（主要导师）领导 和Theoklis Zaoutis，MD，MSCE（共同导师）。他的多学科导师团队，由国家 临床药理学、传染病、肾脏病学和重症监护医学方面的专家， 费城儿童医院和费城大学的特殊研究环境 宾夕法尼亚州，将提供资源和内容的专业知识，以确保拟议的研究成功 并促进向学术独立的过渡。 拟议的项目旨在提高静脉（IV）万古霉素给药的安全性和疗效， 通过开发一种方法来提供个性化的，以目标为导向的万古霉素给药。这 建议将涉及一系列相关的前瞻性研究，这些研究将导致开发和 实施有效的贝叶斯给药策略，以靶向万古霉素曲线下面积（AUC 24）， 重症患儿。目的1将生成IV万古霉素的群体PK模型，包括新的肾脏 损伤生物标志物作为协变量。目标2将确定使用贝叶斯估计AUC 24的最佳采样时间 估计（目标2A），然后在一个单独的儿童队列中验证最佳采样时间（目标2B）。目的 3将试验贝叶斯给药的可行性，以在危重儿科患者中达到目标AUC 24目标 使用实时生物标志物和万古霉素测量和剂量调整。这一建议，结合 在药物计量学和临床研究方面的教学培训和强大的指导，将为唐斯博士提供 在儿科临床药理学和感染性疾病方面的独立研究事业的基础 疾病这项研究将导致未来试验的发展，调查个性化的能力， 抗菌剂量和选择，以最大限度地提高治疗效果，降低毒性，并最大限度地减少 在接受万古霉素的儿童中产生耐药性。在此职业发展过程中学到的技能 该奖项将推广到其他抗菌药物和儿科人群的研究。

PROJECT SUMMARY/ABSTRACT The candidate for this K23 Career Development Award, Kevin J. Downes, MD is a pediatric infectious diseases specialist with training in pediatric clinical pharmacology and a background in clinical research focusing on antimicrobial pharmacokinetics/pharmacodynamics (PK/PD) and antibiotic-associated acute kidney injury (AKI). Dr. Downes' long-term career goal is to become an independent investigator with expertise in both pharmacometrics and clinical trials. The proposed mentored research and career development plan promote this career goal by facilitating Dr. Downes' short-term goal to obtain didactic and experiential training in parametric and nonparametric population PK modeling and simulation, Bayesian adaptive control, and clinical trial design. He has assembled a strong team of mentors led by Athena Zuppa MD, MSCE (primary mentor) and Theoklis Zaoutis, MD, MSCE (co-mentor). His multidisciplinary mentorship team, comprised of national experts in clinical pharmacology, infectious diseases, nephrology, and critical care medicine, combined with the exceptional research environment of the Children's Hospital of Philadelphia and the University of Pennsylvania, will provide the resources and content expertise to ensure success of the proposed research and facilitate transition to academic independence. The proposed project seeks to improve the safety and efficacy of intravenous (IV) vancomycin administration in critically children by developing an approach to provide personalized, target-oriented vancomycin dosing. This proposal will involve a series of related prospective studies that will result in the development and implementation of an effective Bayesian dosing strategy to target vancomycin area under the curve (AUC24) in critically ill children. Aim 1 will generate a population PK model for IV vancomycin, incorporating novel kidney injury biomarkers as covariates. Aim 2 will identify the optimal sampling time to estimate AUC24 using Bayesian estimation (Aim 2A) and then validate the optimal sampling time (Aim 2B) in a separate cohort of children. Aim 3 will pilot the feasability of Bayesian dosing to attain a targeted AUC24 goal in critically ill pediatric patients using real-time biomarker and vancomycin measurement and dosing adjustments. This proposal, combined with didactic training and strong mentorship in pharmacometrics and clinical research, will provide Dr. Downes with the foundation for an independent research career in pediatric clinical pharmacology and infectious diseases. This research will lead to development of future trials that investigate the ability of personalized antimicrobial dosing and selection to maximize treatment efficacy, decrease toxicity, and minimize the development of resistance in children receiving vancomycin. The skills learned during this career development award will be generalizable to the study of other antimicrobial agents and pediatric populations.