Optimizing Vancomycin Therapy in Children

优化儿童万古霉素治疗

基本信息

批准号：
10438596
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-10 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438596
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

项目摘要

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.

项目概要/摘要本次 K23 职业发展奖候选人 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和临床研究背景的专家抗菌药物药代动力学/药效学 (PK/PD) 和抗生素相关的急性肾损伤（阿基）。唐斯博士的长期职业目标是成为一名具有两方面专业知识的独立调查员药理学和临床试验。拟议的指导研究和职业发展计划促进通过促进唐斯博士获得以下方面的教学和体验式培训的短期目标来实现这一职业目标参数和非参数群体 PK 建模和模拟、贝叶斯自适应控制和临床试验设计。他组建了一支由 Athena Zuppa MD、MSCE（主要导师）领导的强大导师团队和 Theoklis Zaoutis，医学博士、MSCE（联合导师）。他的多学科指导团队由国家级专家组成临床药理学、感染病学、肾病学、重症医学等专家联合费城儿童医院和费城大学卓越的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。拟议项目旨在提高静脉注射（IV）万古霉素的安全性和有效性通过开发一种提供个性化、有针对性的万古霉素剂量的方法来针对儿童进行关键治疗。这提案将涉及一系列相关的前瞻性研究，这些研究将导致开发和实施有效的贝叶斯给药策略，以万古霉素曲线下面积（AUC24）为目标危重儿童。目标 1 将生成 IV 万古霉素的群体 PK 模型，并结合新型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 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采样时间（目标 2B）。目的 3 将试验贝叶斯给药的可行性，以实现危重儿科患者的 AUC24 目标使用实时生物标志物和万古霉素测量和剂量调整。该提案综合通过在药理学和临床研究方面的教学培训和强有力的指导，唐斯博士将为为儿科临床药理学和传染病的独立研究生涯奠定了基础疾病。这项研究将导致未来试验的发展，以调查个性化的能力抗菌药物的剂量和选择，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的儿童出现耐药性。在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。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Optimizing Vancomycin Therapy in Critically Ill Children: A Population Pharmacokinetics Study to Inform Vancomycin Area under the Curve Estimation Using Novel Biomarkers.

DOI：
10.3390/pharmaceutics15051336
发表时间：
2023-04-25
期刊：
Pharmaceutics
影响因子：
5.4
作者：
Downes KJ;Zuppa AF;Sharova A;Neely MN
通讯作者：
Neely MN

Development and validation of a volumetric absorptive microsampling- liquid chromatography mass spectrometry method for the analysis of cefepime in human whole blood: Application to pediatric pharmacokinetic study.

用于分析人全血中头孢吡肟的体积吸收微量采样-液相色谱质谱法的开发和验证：在儿科药代动力学研究中的应用。

DOI：
10.1016/j.jpba.2019.113002
发表时间：
2020
期刊：
Journal of pharmaceutical and biomedical analysis
影响因子：
3.4
作者：
Moorthy,GaneshS;Vedar,Christina;Zane,NicoleR;Downes,KevinJ;Prodell,JaniceL;DiLiberto,MaryAnn;Zuppa,AthenaF
通讯作者：
Zuppa,AthenaF

Procalcitonin in Pediatric Sepsis: What Is It Good for?