This Mentored Patient-Oriented Research Career Development Award will provide a structured environment with expert mentorship to enable Dr. Christoph Hornik to develop as an independent investigator and future leader in the field of clinical pharmacology in critically ill children. Critical illness leads to substantial physiologic alterations which affect drug disposition. Failure to account for these alterations can result in inadequate dosing with therapeutic failures or drug toxicities. This risk is particularly high in critically ill neonates undergoing cardiac surgery requiring cardiopulmonary bypass; maturational changes in drug disposition, complex underlying disease with abnormal anatomy, and physiologic changes induced by the cardiopulmonary bypass procedure combine to significantly alter drug disposition. Despite its significance, the underlying mechanisms responsible for this altered drug disposition are virtually unknown. Given the lifesaving nature of cardiopulmonary bypass in this critically ill population, elucidating these mechanism is an important public health need. Dr. Hornik proposes to respond to this need by using a systematic approach combining advanced population pharmacokinetic/pharmacodynamic (PK/PD) modeling, biomarkers, and clinically meaningful endpoints. He will test the proposed platform using the probe drug methylprednisolone, which is routinely administered to neonates on cardiopulmonary bypass despite lack of population specific PK/PD data. He will first conduct a PK trial of methylprednisolone in neonates undergoing cardiac surgery requiring cardiopulmonary bypass (Aim1).This trial will leverage the infrastructure of an ongoing multicenter opportunistic PK trial conducted by the Pediatric Trials Network. Next, he will develop a population PK/PD model of methylprednisolone using inflammatory biomarkers to characterize the exposure efficacy relationship (Aim 2). Last, he will use the developed PK/PD model to predict drug exposures and associate them with adverse events recorded in clinical trials previously conducted by his mentors (Aim 3). Dr. Hornik developed a multidisciplinary career development plan that will leverage the resources of both Duke University, where he is an assistant professor of pediatrics, and the University of North Carolina at Chapel Hill, where he is enrolled in a PhD program in pharmaceutical sciences. The combination of structured and rigorous coursework of the PhD program with practical training provided by the aims of this proposal, will allow Dr. Hornik to develop the skills necessary to become an independent researcher and leader of a pediatric clinical pharmacology research team. To guide him through this academic development, Dr. Hornik has assembled an experienced mentorship team with expertise in pediatric pharmacology, mechanistic modeling, biomarkers, and clinical trials, and a history of successful mentorship of junior faculty. Upon successful completion of the proposed Mentored Patient-Oriented Research Career Development Award, Dr. Hornik will have acquired the necessary advanced PK/PD modeling and clinical trial skills to pursue a lifelong career developing safe and effective drugs for use in critically ill children. Further, he will have met his short-term goal of establishing a systematic approach to evaluate drug disposition, efficacy, and safety in neonates undergoing cardiac surgery requiring cardiopulmonary bypass.

Public Health Relevance

Drug dosing in critically ill neonates is often extrapolated from older, healthier children or adults. This approach fails to account for the substantial physiologic alterations resulting from neonatal critical illness. These changes can affect drug disposition leading to therapeutic failures or toxicities. This proposal w ill use adv anced pharmacokinetic/pharmacodynamic modeling techniques to establish a systematic approach to evaluate drug disposition in a particularly vulnerable neonatal population, those undergoing cardiac surgery requiring cardiopulmonary bypass.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HD090239-02
Application #
9529668
Study Section
National Institute of Child Health and Human Development Initial Review Group (CHHD)
Program Officer
Taylor-Zapata, Perdita
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Maharaj, Anil R; Gonzalez, Daniel; Cohen-Wolkowiez, Michael et al. (2018) Improving Pediatric Protein Binding Estimates: An Evaluation of ?1-Acid Glycoprotein Maturation in Healthy and Infected Subjects. Clin Pharmacokinet 57:577-589
Autmizguine, Julie; Melloni, Chiara; Hornik, Christoph P et al. (2018) Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children. Antimicrob Agents Chemother 62:
Thompson, Elizabeth J; Greenberg, Rachel G; Kumar, Karan et al. (2018) Association between Furosemide Exposure and Patent Ductus Arteriosus in Hospitalized Infants of Very Low Birth Weight. J Pediatr 199:231-236
Sherwin, Jennifer; Thompson, Elizabeth; Hill, Kevin D et al. (2018) Clinical pharmacology considerations for children supported with ventricular assist devices. Cardiol Young 28:1082-1090
Puia-Dumitrescu, Mihai; Bretzius, Olivia M; Brown, Nia et al. (2018) Evaluation of Gentamicin Exposure in the Neonatal Intensive Care Unit and Hearing Function at Discharge. J Pediatr 203:131-136
Kumar, Karan R; Clark, David A; Kim, Evan M et al. (2018) Association of Atrial Septal Defects and Bronchopulmonary Dysplasia in Premature Infants. J Pediatr 202:56-62.e2
Ge, Shufan; Beechinor, Ryan J; Hornik, Christoph P et al. (2018) External Evaluation of a Gentamicin Infant Population Pharmacokinetic Model Using Data from a National Electronic Health Record Database. Antimicrob Agents Chemother 62:
Hornik, Christoph P; Gonzalez, Daniel; van den Anker, John et al. (2018) Population Pharmacokinetics of Intramuscular and Intravenous Ketamine in Children. J Clin Pharmacol :
Hornik, Christoph P; Onufrak, Nikolas J; Smith, P Brian et al. (2018) Association between oral sildenafil dosing, predicted exposure, and systemic hypotension in hospitalised infants. Cardiol Young 28:85-92
Barker, Piers C A; Tatum, Gregory H; Campbell, Michael J et al. (2018) Improving maternal-infant bonding after prenatal diagnosis of CHD. Cardiol Young 28:1306-1315

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