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30%的婴儿 因SVD导致的心力衰竭住院死亡，25%的人需要心脏移植。这种令人无法接受的发病率 而死亡率是由于SVD的解剖异常对婴儿心肌造成不利的负荷，以及 在这群人中，缺乏药物被证明是有效的。婴幼儿心力衰竭的失神治疗 SVD是一种公共卫生危机，需要采取紧急和系统的应对措施来解决药物开发问题 这群人面临的挑战。最近，Na+/K+-ATPase抑制剂地高辛是有史以来发现的第一种药物 改善SVD婴儿存活率的回顾性研究。尽管这一发现很有希望，但治疗失败 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是由于 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 是一种治疗指标较窄的药物，可通过肾小球滤过消除肾功能。而药代动力学(PK)和 暴露靶标在成人中已知，地高辛的PK和药效学(PD)尚未在#年进行研究 婴儿患有SVD。在这个种群中，生长和成熟与疾病的病理生理动态地相互作用 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，而婴儿心肌细胞，地高辛靶向，在结构上，代谢上，和 因不成熟和SVD而发生功能改变。尽管还不完全理解，但这些相互作用可能会影响 地高辛通过不同的暴露、反应或两者兼而有之而产生疗效。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促进发展至关重要 为患有SVD的婴儿开发新的心力衰竭药物。尽管有很高的

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