Pharmacology of Aminophylline for Acute Kidney Injury in Neonates and Children

氨茶碱治疗新生儿和儿童急性肾损伤的药理学

• 批准号: 9242677
• 负责人: Adam Frymoyer
• 金额: $ 16.82万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242677
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Aminophylline; Applications Grants; Award; Biological Markers; Blood; California; Cardiac Surgery procedures; Cardiopulmonary Bypass; Child; Child health care; Childhood; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials; Clinical and Translational Science Awards; Controlled Clinical Trials; Creatinine; Critical Illness; Custom; Cytochrome P450; Data; Decision Making; Detection; Development; Development Plans; Diagnosis; Dose; Double-Blind Method; Drug Kinetics; Drug usage; Excretory function; Faculty; Feedback; Functional disorder; Funding; Future; Goals; Hospitals; Incidence; Infant; Injury; Institution; International; Intervention Studies; Ischemia; Kidney; Knowledge; LCN2 gene; Lead; Measurement; Measures; Mediating; Mentors; Mentorship; Modeling; Monitor; Morbidity - disease rate; Near-Infrared Spectroscopy; Neonatal; Neonatal Intensive Care Units; Operative Surgical Procedures; Pathway interactions; Pediatric Hospitals; Perfusion; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Placebo Control; Plasma; Population; Positioning Attribute; Prospective Studies; Protein Isoforms; Public Health; Purinergic P1 Receptors; Randomized; Randomized Controlled Trials; Renal function; Research; Research Design; Research Personnel; Research Training; Resources; Role; Safety; Sampling; San Francisco; Serum; Spottings; Standardization; Structure; Theophylline; Therapeutic; Therapeutic Index; Training; Universities; Urine; career development; clinical Diagnosis; design; drug efficacy; effective therapy; experience; glomerular filtration; improved; inhibitor/antagonist; models and simulation; mortality; multidisciplinary; neonate; novel; patient population; pediatric patients; pharmacodynamic model; pharmacokinetic model; programs; prophylactic; prospective; public health relevance; renal ischemia; simulation; standard of care; targeted treatment; therapy development; treatment response; treatment strategy; urinary; vasoconstriction

DESCRIPTION (provided by applicant): The candidate, Adam Frymoyer MD, is dedicated to advancing public health by promoting the safe and efficacious use of drugs in neonates and children. This K23 proposal will provide a structured clinical research training experience with formal mentorship that will enable Dr. Frymoyer to become an independent clinical researcher with expertise in pediatric clinical pharmacology and pharmacometrics. An integrated, multi- disciplinary pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation framework will be applied to investigate aminophylline as a treatment for acute kidney injury (AKI) in 1) infants and children following cardiac surgery requiring cardiopulmonary bypass (CPB) and 2) neonates with clinically diagnosed AKI. AKI due to renal ischemia is common in critically-ill populations of neonates, infants, and children and is an independent predictor of morbidity and mortality. Currently, there is a gap in therapeutic treatment options available for AKI. Aminophylline, an adenosine receptor inhibitor, may offer a targeted therapeutic strategy improving renal perfusion and limiting further kidney injury. To develop the therapeutic role of aminophylline for AKI in neonates and children, a clear understanding of its PK-PD is critical. This application will take advantage of data collected as part of a prospective randomized placebo-controlled clinical trial examining prophylactic administration of aminophylline for AKI in infants and children following cardiac surgery requiring CPB. In addition, a prospective clinical study examining the PK-PD of aminophylline will be conducted in neonates with AKI. The approach will include use of an opportunistic study design, sparse sampling, micro-volume drug level measurement via dried blood spot (DBS) analysis, and advanced population modeling and simulation. In addition, serum and urinary biomarkers of kidney injury will be applied to assess drug treatment response. The career development activities will capitalize on the rich collaborative network of expertise, mentors, programs, and resources provided by two world-renowned research institutions - Stanford University and University of California San Francisco. The career development plan incorporates didactic and formal coursework in clinical research and advanced population PK-PD modeling and simulation. The assembled mentorship team is uniquely qualified with extensive clinical research experience, including internationally recognized expertise in clinical pharmacology, clinical trials, PK-PD modeling and simulation, and successful mentorship of junior faculty. Dr. Frymoyer will also have access to the resources provided by the Neonatal Intensive Care Unit at Lucile Packard Children's Hospital, and Spectrum Child Health funded by a Clinical Translational Science Award at Stanford University. This research will lead to the development of an interventional study of customized aminophylline dosing strategies for the treatment of AKI in infants and children including a subsequent randomized controlled trial using aminophylline for neonatal AKI. Upon conclusion of the award, Dr. Frymoyer will be optimally positioned to lead a pediatric clinical pharmacology research program.

描述（由申请人提供）：候选人Adam Frymoyer医学博士，致力于通过促进新生儿和儿童安全有效地使用药物来促进公共卫生。该K23提案将提供结构化的临床研究培训经验，并提供正式的指导，这将使Frymoyer博士成为具有儿科临床药理学和药物计量学专业知识的独立临床研究员。一个综合的，多学科的药代动力学-药效学（PK-PD）建模和模拟框架将被应用于研究氨茶碱作为治疗急性肾损伤（AKI）在1)婴儿和儿童心脏手术后需要体外循环（CPB）和2)新生儿临床诊断为AKI。肾缺血引起的AKI在新生儿、婴儿和儿童的危重人群中很常见，是发病率和死亡率的独立预测因子。目前，AKI的治疗方案存在空白。氨茶碱是一种腺苷受体抑制剂，可能提供一种改善肾灌注和限制进一步肾损伤的靶向治疗策略。为了开发氨茶碱在新生儿和儿童AKI中的治疗作用，明确其PK-PD是至关重要的。该应用程序将利用作为前瞻性随机安慰剂对照临床试验的一部分收集的数据，该试验检查了在美国预防使用氨茶碱治疗AKI的方法