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Digoxin Pharmacodynamics in Infants with Heart Failure due to Single Ventricle Congenital Heart Disease

Award Number: R01HD106588
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Digoxin Pharmacodynamics in Infants with Heart Failure due to Single Ventricle Congenital Heart Disease - In infants with single ventricle congenital heart disease (SVD), heart failure is deadly. Each year 30% of infants hospitalized with heart failure due to SVD die, and 25% require cardiac transplant. This unacceptable morbidity and mortality is due to both the anatomic abnormalities of SVD unfavorably loading the infant myocardium, and the lack of drugs proven efficacious in this population. The absence heart failure therapeutics in infants with SVD is a public health crisis, necessitating an urgent and systematic response to address drug development challenges in this population. Recently, the Na+/K+-ATPase inhibitor digoxin was the first ever drug found in retrospective studies to improve survival in infants with SVD. Despite this promising finding, therapeutic failures occurred. While the cause of failures may be multifactorial, the experience with digoxin in heart failure due to SVD illustrates the knowledge gaps and limitations of current pediatric heart failure drug development. Digoxin is a narrow therapeutic index drug renally eliminated via glomerular filtration. While pharmacokinetics (PK) and exposure targets are known in adults, the PK and pharmacodynamics (PD) of digoxin have not been studied in infants with SVD. In this population, growth and maturation dynamically interact with disease pathophysiologic changes to affect drug disposition and response. For digoxin, renal maturation and kidney injury oppositely affect drug exposure, while the infantile cardiomyocyte, the digoxin target, is structurally, metabolically, and functionally altered by immaturity and SVD. Though incompletely understood, these interactions likely affect digoxin efficacy through differing exposure, response, or both. Understanding how ontogeny and disease interact to alter drug exposure and response is essential to reducing treatment failures and inform development of new heart failure drugs for infants with SVD. Despite the high


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Child Health and Human Development Extramural Research	000	3	3/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $629,432 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Child Health and Human Development Extramural Research	001	3	3/4/2024	NON-COMPETING CONTINUATION	$0
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Child Health and Human Development Extramural Research	002	3	7/8/2024	NON-COMPETING CONTINUATION	$57,221
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Child Health and Human Development Extramural Research	000	3	2/29/2024	NON-COMPETING CONTINUATION	$572,211
														Subtotal = $629,432

Issue Date FY: 2023 ( Subtotal = $551,975 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Child Health and Human Development Extramural Research	001	2	5/2/2023	NON-COMPETING CONTINUATION	$0
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Child Health and Human Development Extramural Research	000	2	3/11/2023	NON-COMPETING CONTINUATION	$551,975
														Subtotal = $551,975

Issue Date FY: 2022 ( Subtotal = $649,188 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Child Health and Human Development Extramural Research	000	1	4/2/2022	NEW	$649,188
														Subtotal = $649,188

Grand Total All Awards = $1,830,595

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Digoxin Pharmacodynamics in Infants with Heart Failure due to Single Ventricle Congenital Heart Disease

Award Number: R01HD106588

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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