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

地高辛在单心室先天性心脏病心力衰竭婴儿中的药效学

基本信息

批准号：
10464211
负责人：
Christoph Hornik
金额：
$ 64.92万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10464211
关键词：
ATPase inhibitory protein Accounting Address Adult Affect Age Age-Months Area Biological Markers Brain natriuretic peptide Cardiac Cardiac Death Cardiac Myocytes Cardiac Surgery procedures Cessation of life Characteristics Child Childhood Clinical Clinical Data Clinical Research Complex Deformity Development Digoxin Disease Doctor of Philosophy Dose Drug Exposure Drug Kinetics Echocardiography Environment Equation Event Failure Goals Growth Half-Life Heart Transplantation Heart failure Image Infant Injury to Kidney Kidney Knowledge Measures Metabolic Morbidity - disease rate Myocardium N-terminal National Institute of Child Health and Human Development Network Infrastructure Outcome Pathologic Patients Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Pharmacotherapy Physiological Plasma Population Population Growth Principal Investigator Public Health Recording of previous events Renal function Research Research Institute Retrospective Studies Science Single ventricle congenital heart disease Surrogate Markers Symptoms Therapeutic Therapeutic Index Treatment Failure Validation data access dosage drug action drug development drug disposition experience glomerular filtration heart function heart imaging imaging biomarker improved infancy kidney pharmacology member model development mortality multidisciplinary neonate novel strategies pediatric heart failure pharmacodynamic model pharmacokinetics and pharmacodynamics predictive modeling prospective response skills therapeutic development

项目摘要

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

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