Pharmacology of Aminophylline for Acute Kidney Injury in Neonates and Children

描述（由申请人提供）：候选人，亚当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，使Frymoyer博士能够成为一名独立的临床研究人员，拥有儿科临床药理学和药物计量学方面的专业知识。将应用综合的多学科药代动力学-药效学（PK-PD）建模和模拟框架，研究氨茶碱作为1）需要体外循环（CPB）的心脏手术后婴儿和儿童以及2）临床诊断为阿基的新生儿的急性肾损伤（阿基）治疗。肾缺血引起的阿基常见于新生儿、婴儿和儿童的危重人群，是发病率和死亡率的独立预测因素。目前，阿基可用的治疗性治疗选择存在差距。氨茶碱是一种腺苷受体抑制剂，可能提供一种靶向治疗策略，改善肾灌注并限制进一步的肾损伤。为了开发氨茶碱对新生儿和儿童阿基的治疗作用，明确了解其PK-PD至关重要。本申请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，该临床试验检查了氨茶碱预防性给药用于阿基， 婴儿和儿童心脏手术后需要CPB。此外，将在阿基新生儿中开展一项前瞻性临床研究，检查氨茶碱的PK-PD。该方法将包括使用机会性研究设计、稀疏采样、通过干血斑（DBS）分析进行微量药物水平测量以及高级群体建模和模拟。此外，将采用肾损伤的血清和尿液生物标志物评估药物治疗反应。职业发展活动将利用两个世界知名的研究机构--斯坦福大学和加州旧金山弗朗西斯科提供的丰富的专业知识、导师、项目和资源合作网络。职业发展计划包括临床研究和高级人群PK-PD建模和模拟的教学和正式课程。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，以及初级教师的成功导师。Frymoyer博士还将获得Lucile Packard儿童医院新生儿重症监护室提供的资源，以及斯坦福大学临床转化科学奖资助的Spectrum儿童健康项目。这项研究将导致制定一项干预性研究，为婴儿和儿童阿基的治疗提供定制的氨茶碱给药策略，包括随后使用氨茶碱治疗新生儿阿基的随机对照试验。获奖后，Frymoyer博士将最适合领导儿科临床药理学研究项目。

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.