Optimizing Vancomycin Therapy in Children

优化儿童万古霉素治疗

• 批准号: 10201690
• 负责人: Kevin James Downes
• 金额: $ 14.94万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-10 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201690
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adverse drug event; Age; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Area Under Curve; Bayesian Analysis; Bayesian Method; Biological Markers; Blood; Blood specimen; Cause of Death; Characteristics; Child; Childhood; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials; Clinical Trials Design; Communicable Diseases; Computer software; Creatinine; Critical Care; Critical Illness; Critically ill children; Data; Development; Development Plans; Dose; Drug Kinetics; Drug Monitoring; Ensure; Environment; Exhibits; Foundations; Future; Goals; Health; Hospital Mortality; Infection; Injury to Kidney; Intravenous; K-Series Research Career Programs; LCN2 gene; Lead; Measurement; Measures; Medicine; Mentors; Mentorship; Methods; Modeling; Nephrology; Outcome; Patients; Pediatric Hospitals; Pediatric Intensive Care Units; Pennsylvania; Pharmaceutical Preparations; Philadelphia; Pilot Projects; Plasma; Population; Prospective Studies; Prospective cohort; Public Health; Recording of previous events; Renal function; Research; Research Personnel; Research Proposals; Resistance development; Resources; Risk Factors; Safety; Sampling; Sepsis; Series; Serum; Specialist; Testing; Therapeutic; Time; Toxic effect; Training; Treatment Efficacy; Treatment Failure; Universities; Validation; Vancomycin; antimicrobial; antimicrobial drug; base; career; career development; cohort; control trial; design; dosage; drug clearance; effective therapy; high risk; improved; models and simulation; mortality; multidisciplinary; novel; novel marker; osteopontin; pediatric patients; pharmacokinetic model; pharmacokinetics and pharmacodynamics; pharmacometrics; post gamma-globulins; predictive modeling; prevent; prospective; research and development; skills; success; therapeutic target; urinary

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.

项目摘要/摘要 该K23职业发展奖的候选人Kevin J. Downes，医学博士是儿科传染病 小儿临床药理学培训和临床研究背景的专家 抗菌药代动力学/药效学（PK/PD）和抗生素相关的急性肾脏损伤 （aki）。唐斯博士的长期职业目标是成为具有专业知识的独立调查员 药物测量和临床试验。拟议的指导研究和职业发展计划促进 通过促进唐斯博士的短期目标，以获得教学和体验培训，以实现这一职业目标 参数和非参数种群PK建模和模拟，贝叶斯自适应控制以及临床 试用设计。他组建了一个由雅典娜·祖帕（Athena Zuppa）医学博士（MSCE）（主要导师）领导的强大导师团队 和MSCE医学博士Theoklis Zaoutis。他的多学科指导团队由国家组成 临床药理学，传染病，肾脏病和重症监护医学专家 费城儿童医院和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 并促进过渡到学术独立性。 拟议的项目旨在提高静脉（IV）万古霉素给药的安全性和功效 通过开发一种提供个性化的，面向目标的万古霉素剂量的方法来关键儿童。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 实施有效的贝叶斯剂量策略，以靶向曲线下的万古霉素区域（AUC24） 重病的孩子。 AIM 1将为IV Vansycin产生人群PK模型，并结合新型肾脏 伤害生物标志物作为协变量。 AIM 2将确定使用贝叶斯估算AUC24的最佳抽样时间 估计（AIM 2A），然后在单独的儿童队列中验证最佳采样时间（AIM 2B）。目的 3将试用贝叶斯剂量的可行性，以实现针对性病患儿科患者的目标AUC24目标 使用实时生物标志物和万古霉素的测量和给药调整。该提议合并 通过教学培训和药物计量学和临床研究的强大指导，将为唐斯博士提供 凭借小儿临床药理学和感染性的独立研究生涯的基础 疾病。这项研究将导致未来的试验发展，以调查个性化的能力 抗菌剂量和选择，以最大化治疗功效，降低毒性并最小化治疗功效 接受万古霉素儿童的抗药性。在这一职业发展中学到的技能 奖项将推广到对其他抗菌药物和小儿种群的研究。