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
