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.

申请人描述：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健康。这项K23计划将在正式指导下提供结构化的临床研究培训经验，使Frymoyer博士能够成为一名独立的临床研究人员，具有儿科临床药理学和药物计量学方面的专业知识。一个整合的多学科药代动力学-药效学(PK-PD)建模和模拟框架将用于研究氨茶碱对1)需要体外循环(CPB)的心脏手术后的婴儿和儿童以及2)临床诊断为AKI的新生儿的急性肾损伤(AKI)的治疗作用。肾缺血引起的急性心肌梗死在新生儿、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的治疗选择存在缺口。氨茶碱是一种腺苷受体抑制剂，它可能提供一种靶向治疗策略，改善肾脏血流灌注，限制进一步的肾脏损伤。为了开发氨茶碱对新生儿和儿童AKI的治疗作用，对其PK-PD的清楚了解是至关重要的。这一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，该临床试验检查AKI患者预防性给予氨茶碱。 需要体外循环的心脏手术后的婴幼儿。此外，还将对AKI新生儿进行氨茶碱的PK-PD前瞻性临床研究。该方法将包括使用机会主义研究设计、稀疏抽样、通过干血斑点(DBS)分析测量微量药物水平，以及先进的总体建模和模拟。此外，还将应用肾损伤的血清和尿液生物标志物来评估药物治疗反应。职业发展活动将利用两家世界知名研究机构-斯坦福大学和加州大学旧金山分校-提供的丰富的专业知识、导师、项目和资源的合作网络。职业发展计划结合了临床研究和高级人群PK-PD建模和模拟方面的授课和正式课程。组建的导师团队具有丰富的临床研究经验，包括国际公认的临床药理学、临床试验、PK-PD建模和模拟方面的专业知识，以及对初级教师的成功指导。Frymoyer博士还将获得Lucile Packard儿童医院新生儿重症监护病房和斯坦福大学临床转化科学奖资助的Spectrum儿童健康中心提供的资源。这项研究将导致对定制的氨茶碱剂量策略用于治疗婴儿和儿童AKI的干预性研究的发展，包括随后使用氨茶碱治疗新生儿AKI的随机对照试验。获奖后，弗莱莫耶博士将处于领导儿科临床药理学研究项目的最佳位置。