Population Pharmacokinetics of Caffeine in Neonates with Congenital Heart Disease and Associations with Acute Kidney Injury.
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2024-03
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Abstract
Cardiac surgery-associated acute kidney injury (CS-AKI) occurs in approximately 65% of neonates undergoing cardiac surgery on cardiopulmonary bypass and contributes to morbidity and mortality. Caffeine may reduce CS-AKI by counteracting adenosine receptor upregulation after bypass, but pharmacokinetics (PK) in this population are unknown. The goal of our analysis is to address knowledge gaps in age-, disease-, and bypass-related effects on caffeine disposition and explore preliminary associations between caffeine exposure and CS-AKI using population PK modeling techniques and an opportunistic, electronic health record-integrated trial design. We prospectively enrolled neonates receiving preoperative caffeine per standard of care and collected PK samples. We retrospectively identified neonates without caffeine exposure undergoing surgery on bypass as a control cohort. We followed US Food and Drug Administration guidance for population PK model development using NONMEM. Effects of clinical covariates on PK parameters were evaluated. We simulated perioperative exposures and used multivariable logistic regression to evaluate the association between caffeine exposure and CS-AKI. Twenty-seven neonates were included in model development. A 1-compartment model with bypass time as a covariate on clearance and volume of distribution best fit the data. Twenty-three neonates with caffeine exposure and 109 controls were included in the exposure-response analysis. Over half of neonates developed CS-AKI. On multivariable analysis, there were no significant differences between CS-AKI with and without caffeine exposure. Neonates with single-ventricle heart disease without CS-AKI had consistently higher simulated caffeine exposures. Our results highlight areas for further study to better understand disease- and bypass-specific effects on drug disposition and identify populations where caffeine may be beneficial.
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Thompson, Elizabeth J, Kanecia O Zimmerman, Daniel Gonzalez, Henry P Foote, Sangah Park, Kevin D Hill, Jillian H Hurst, Chi D Hornik, et al. (2024). Population Pharmacokinetics of Caffeine in Neonates with Congenital Heart Disease and Associations with Acute Kidney Injury. Journal of clinical pharmacology, 64(3). pp. 300–311. 10.1002/jcph.2382 Retrieved from https://hdl.handle.net/10161/33608.
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Scholars@Duke
Elizabeth Thompson
Kanecia Obie Zimmerman
Daniel Gonzalez
Dr. Daniel Gonzalez is an Associate Professor in the Division of Clinical Pharmacology of the Department of Medicine at the Duke University School of Medicine, and a member of the Duke Clinical Research Institute. He also has a secondary appointment in the Department of Pharmacology and Cancer Biology. Dr. Gonzalez received his PharmD and PhD from the University of Florida College of Pharmacy in 2008 and 2012, respectively. He then completed a postdoctoral fellowship through the UNC-Duke Collaborative Clinical Pharmacology T32 Postdoctoral Training Program. Following completion of his post-doctoral training, Dr. Gonzalez served as a faculty member at the UNC Eshelman School of Pharmacy between 2014 and 2023 and moved to Duke University in 2023.
Dr. Gonzalez’s experiences have afforded a highly collaborative and multidisciplinary research program focused on advancing public health by promoting the safe, effective, and individualized use of drugs, with an emphasis on pediatric populations. His research interests include clinical pharmacology and applying mathematical modeling and simulation techniques to characterize the pharmacokinetics and pharmacodynamics of drugs, guide drug dosage selection, and improve drug safety. Dr. Gonzalez’s research program is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and he has published >115 peer-reviewed publications and >40 abstracts. He has been the major advisor for 8 PhD students (5 completed, 3 in training) and 15 postdoctoral fellows.
Henry Foote
Kevin Dennis Hill
Clinical research including outcomes, drug and device trials, short and long term safety and efficacy of interventions and hemodynamic effects of interventions.
Jillian Hurst
Intersections of the upper respiratory microbiome, environmental exposures, and childhood respiratory infections
Early life exposure to and colonization with microbes has a profound influence on the education of the immune system and susceptibility to viral and bacterial infections later in life. My research is focused on the influence of the upper respiratory microbiome on the development of recurrent respiratory infections, including acute otitis media (AOM), the leading cause of antibiotic prescriptions and healthcare consultations among children. Importantly, some children develop recurrent infections that are thought to be linked to dysbiosis of the nasopharyngeal microbiome. My overarching goals are to identify alterations in the upper respiratory microbiome associated with AOM and to elucidate host factors and exposures that predispose some children to the development of recurrent AOM episodes.
Children's Health & Discovery Initiative:
The prenatal period, infancy, childhood, and adolescence, represent critical time periods of human development that include more developmental milestones than any other period of the lifespan. Conditions during these developmental windows – including biological, social, economic, health, and environmental factors – have a profound impact on lifelong health. The Children’s Health and Discovery Initiative (CHDI) was founded on the hypothesis that interventions early in life will improve population health across the lifespan. To this end, the overarching goal of the CHDI is to create a robust coalition of multidisciplinary investigators and a pipeline of infrastructure, data, and research projects focused on developing innovative approaches to identifying and modulating early life factors that impact lifelong health and well-being.
Chi Hornik
Chi Hornik is the Director of Heart Center Research and the Director of Critical Care Medicine Research in the Department of Pediatrics. She is an Associate Professor in the Duke School of Medicine and a member of the Duke Clinical Research Institute (DCRI). She serves as Principal Investigator (PI) of Duke as a site for numerous studies and as clinical coordinating center PI of multi-center trials through the DCRI. As a clinical specialist in neonatal and pediatric critical care, she is dedicated to advancing drug and device development. She ensures that the research encompasses patients who are representative of the disease or condition being studied. Her commitment is to advance health outcomes for all children, striving for equity in clinical research.
Reid C Chamberlain
Dr. Chamberlain is currently one of the Department of Pediatrics Chief Residents, which he started after completing his pediatric residency training at Duke University in 2015. In 2016, he will begin fellowship training in pediatric cardiology at Duke.
Rasheed Adebayo Gbadegesin
Molecular genetics of glomerular disease
Genetic risk factors for childhood onset idiopathic nephrotic syndrome
Christoph Paul Vincent Hornik
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