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.

Public Health Relevance

Acute kidney injury (AKI) in critically ill neonates and children is common and associated with significant morbidity and mortality. No targeted therapeutic treatment strategies have been established for AKI in pediatric patients. Within a clinical pharmacokinetic and pharmacodynamic conceptual framework, this project will examine the medication aminophylline as a potential novel treatment approach for AKI. In addition, the application will address the enormous shortage of formally trained clinical pharmacologists needed to focus on the unique therapeutic needs of neonates and children.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Mentored Patient-Oriented Research Career Development Award (K23)
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Biobehavioral and Behavioral Sciences Subcommittee (CHHD)
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Zajicek, Anne
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Stanford University
Schools of Medicine
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Piester, Travis; Frymoyer, Adam; Christofferson, Megan et al. (2018) A Mobile Infliximab Dosing Calculator for Therapy Optimization in Inflammatory Bowel Disease. Inflamm Bowel Dis 24:227-234
Frymoyer, Adam; Hoekman, Daniƫl R; Piester, Travis L et al. (2017) Application of Population Pharmacokinetic Modeling for Individualized Infliximab Dosing Strategies in Crohn Disease. J Pediatr Gastroenterol Nutr 65:639-645
Frymoyer, Adam; Bonifacio, Sonia L; Drover, David R et al. (2017) Decreased Morphine Clearance in Neonates With Hypoxic Ischemic Encephalopathy Receiving Hypothermia. J Clin Pharmacol 57:64-76
Frymoyer, Adam; Juul, Sandra E; Massaro, An N et al. (2017) High-dose erythropoietin population pharmacokinetics in neonates with hypoxic-ischemic encephalopathy receiving hypothermia. Pediatr Res 81:865-872
Frymoyer, Adam; Su, Felice; Grimm, Paul C et al. (2016) Theophylline Population Pharmacokinetics and Dosing in Children Following Congenital Heart Surgery With Cardiopulmonary Bypass. J Clin Pharmacol 56:1084-93
Frymoyer, Adam; Piester, Travis L; Park, K T (2016) Infliximab Dosing Strategies and Predicted Trough Exposure in Children With Crohn Disease. J Pediatr Gastroenterol Nutr 62:723-7
Stockmann, Chris; Hersh, Adam L; Roberts, Jessica K et al. (2015) Predictive Performance of a Vancomycin Population Pharmacokinetic Model in Neonates. Infect Dis Ther 4:187-98
Das, Millie; Padda, Sukhmani K; Frymoyer, Adam et al. (2015) Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction. Lung Cancer 89:280-6
Trachtman, H; Frymoyer, A; Lewandowski, A et al. (2015) Pharmacokinetics, Pharmacodynamics, and Safety of Lisinopril in Pediatric Kidney Transplant Patients: Implications for Starting Dose Selection. Clin Pharmacol Ther 98:25-33