Optimizing Vancomycin Therapy in Children

项目摘要/摘要 本次K23职业发展奖的候选人Kevin J.Downes医学博士是一名儿科传染病专家 受过儿科临床药理学培训并有临床研究背景的专家，专注于 抗菌药物药代动力学/药效学(PK/PD)与抗生素相关性急性肾损伤 (Aki)。唐斯博士的长期职业目标是成为一名在这两方面都有专长的独立调查员 药物计量学和临床试验。拟议的导师研究和职业发展计划促进 这一职业目标是通过促进唐斯博士的短期目标来获得指导性和经验性的 参数和非参数总体PK建模与仿真、贝叶斯自适应控制和临床 试验设计。他组建了一支强大的导师团队，由主要导师雅典娜·祖帕医学博士领导。 和Theoklis Zaoutis，医学博士，MSCe(共同导师)。他的多学科指导团队，由国家 临床药理学、传染病、肾脏病和重症监护医学的专家，与 费城儿童医院和宾夕法尼亚大学的特殊研究环境 宾夕法尼亚州将提供资源和内容专业知识，以确保拟议研究的成功 并促进向学术独立的过渡。 拟议的项目旨在提高静脉注射万古霉素的安全性和有效性。 通过开发一种提供个性化、靶向万古霉素剂量的方法，对儿童进行危重治疗。这 提案将涉及一系列相关的前瞻性研究，这些研究将导致发展和 实施有效的贝叶斯给药策略以靶向万古霉素曲线下面积(AUC24) 病情危重的儿童。目标1将建立万古霉素静脉注射的群体PK模型，结合新的肾脏 伤害生物标志物作为协变量。目标2将确定使用贝叶斯估计AUC24的最佳采样时间 估计(目标2A)，然后在单独的儿童队列中验证最佳抽样时间(目标2B)。目标 3将在危重儿科患者中试验贝叶斯剂量的可行性，以达到目标AUC24 使用实时生物标记物和万古霉素测量和剂量调整。这项建议，结合在一起 通过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学方面拥有独立研究生涯的基础 疾病。这项研究将导致未来研究个性化能力的试验的发展。 抗菌剂的剂量和选择，以最大限度地提高治疗效果，降低毒性，并最大限度地减少 接受万古霉素治疗的儿童的耐药性发展。在职业发展过程中学到的技能 该奖项将推广到其他抗菌剂和儿科人群的研究。

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.