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

在患有单心室先天性心脏病（SVD）的婴儿中，心力衰竭是致命的。每年有30%的婴儿 因瓣膜SVD导致心力衰竭住院患者死亡，25%需要心脏移植。这种不可接受的发病率 死亡率是由于SVD的解剖异常不利地负荷婴儿心肌， 缺乏对这一人群有效的药物。婴幼儿心力衰竭的失神治疗 瓣膜病是一场公共卫生危机，需要采取紧急和系统的应对措施来解决药物开发问题 这个人群的挑战。最近，Na+/K+-ATP酶抑制剂地高辛是第一个发现的药物， 回顾性研究，以提高SVD婴儿的存活率。尽管这一有希望的发现， 发生了。虽然失败的原因可能是多因素的，但地高辛治疗心力衰竭的经验， SVD说明了目前儿科心力衰竭药物开发的知识差距和局限性。地高辛 是一种治疗指数较窄的药物，通过肾小球滤过作用经肾脏消除。而药代动力学（PK）和 已知成人中的暴露目标，尚未在成人中研究地高辛的PK和药效学（PD）。 婴儿SVD在这个群体中，生长和成熟与疾病病理生理学动态相互作用， 影响药物处置和反应的变化。对于地高辛，肾成熟和肾损伤相反 影响药物暴露，而地高辛靶向的婴儿心肌细胞在结构上、代谢上， 功能上被不成熟和SVD改变。虽然还不完全清楚，但这些相互作用可能会影响 地高辛疗效通过不同的暴露，反应，或两者兼而有之。了解个体发育和疾病 相互作用以改变药物暴露和反应对于减少治疗失败和为发展提供信息至关重要 新的心脏衰竭药物治疗SVD婴儿。尽管高

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