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: 8678295
• 负责人: Adam Frymoyer
• 金额: $ 13.19万
• 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/8678295
• 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; 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; Gelatinase A; Goals; Hospitals; Incidence; Infant; Injury; Institution; Intervention Studies; Ischemia; Kidney; Knowledge; Lead; Measurement; Measures; Mediating; Mentors; Mentorship; Modeling; Monitor; Morbidity - disease rate; Near-Infrared Spectroscopy; Neonatal; Neonatal Intensive Care Units; Operative Surgical Procedures; Pathway interactions; Patients; Pediatric Hospitals; Perfusion; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Placebo Control; Plasma; Population; Positioning Attribute; Prospective Studies; Protein Isoforms; Public Health; Purinergic P1 Receptors; Qualifying; Randomized; Randomized Controlled Trials; Renal function; Research; Research Design; Research Personnel; Research Training; Resources; Role; Safety; Sampling; San Francisco; Serum; Spottings; Structure; Theophylline; Therapeutic; Therapeutic Index; Training; Universities; Urine; base; career development; design; effective therapy; experience; glomerular filtration; improved; inhibitor/antagonist; models and simulation; mortality; neonate; novel; patient population; pharmacodynamic model; pharmacokinetic model; programs; prophylactic; prospective; public health relevance; renal ischemia; simulation; standard of care; therapeutic target; 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）：候选人亚当·弗里莫耶（Adam Frymoyer MD）致力于通过促进新生儿和儿童的安全有效使用来推动公共卫生。该K23提案将提供正式指导的结构化临床研究培训经验，这将使Frymoyer博士能够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人员。综合，多学科的药代动力学 - 术语（PK-PD）建模和仿真框架将用于研究氨基氨叶林作为急性肾脏损伤（AKI）的治疗，对1名急性肾脏损伤（AKI）进行治疗，对心脏手术进行急性肾脏损伤（AKI），需要进行心肺旁路（CPB）和2）NEONONATES NEONONATES NEONONATES进行临床诊断。由于肾脏缺血而引起的AKI在新生儿，婴儿和儿童的关键种群中很常见，并且是发病率和死亡率的独立预测指标。目前，AKI可用的治疗方法存在差距。氨基苯胺是一种腺苷受体抑制剂，可以提供针对性的治疗策略，可改善肾脏灌注并限制进一步的肾脏损伤。为了开发氨基氨基氨酸对AKI在新生儿和儿童中的治疗作用，对其PK-PD有清晰的了解至关重要。该应用将利用收集的数据，作为一项前瞻性随机安慰剂对照临床试验的一部分，该试验检查了AKI的预防性给药的预防性给药。 心脏手术后需要CPB的婴儿和儿童。此外，一项前瞻性临床研究检查了氨基氨叶碱的PK-PD，将在AKI的新生儿进行。该方法将包括使用机会研究设计，稀疏采样，通过干血点（DBS）分析的微体积药物水平测量以及高级种群建模和模拟。此外，将应用肾损伤的血清和尿生物标志物评估药物治疗反应。职业发展活动将利用丰富的专业知识，导师，计划和资源的丰富合作网络，由两家世界知名的研究机构（斯坦福大学）和加利福尼亚大学旧金山分校提供。职业发展计划纳入了临床研究和高级人群PK-PD建模和模拟中的教学课程和正式课程。集会的指导团队具有广泛的临床研究经验，包括临床药理学，临床试验，PK-PD建模和模拟以及成功的初级教职指导方面的国际认可的专业知识。 Frymoyer博士还可以访问Lucile Packard儿童医院的新生儿重症监护室提供的资源，以及由斯坦福大学临床转化科学奖资助的Spectrum Child Health。这项研究将导致开发针对婴儿和儿童中AKI的定制氨基叶素剂量策略的介入研究，包括随后的随后使用氨基叶素用于新生儿AKI的随机随机对照试验。该奖项结束后，Frymoyer博士将在领导儿科临床药理学研究计划中最佳地定位。