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

对于患有单心室先天性心脏病 (SVD) 的婴儿，心力衰竭是致命的。每年 30% 的婴儿因 SVD 因心力衰竭住院死亡，25% 需要心脏移植。这种不可接受的发病率和死亡是由于 SVD 的解剖异常给婴儿心肌带来不利的负荷，以及缺乏被证明对这一人群有效的药物。婴儿心力衰竭的治疗 SVD 是一场公共卫生危机，需要采取紧急、系统的应对措施来解决药物开发问题该人群面临的挑战。最近，Na+/K+-ATPase 抑制剂地高辛是第一个发现的药物改善 SVD 婴儿生存率的回顾性研究。尽管有这一有希望的发现，但治疗失败发生。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 SVD 说明了当前儿科心力衰竭药物开发的知识差距和局限性。地高辛是一种窄治疗指数药物，通过肾小球滤过进行肾脏消除。虽然药代动力学 (PK) 和成人中的暴露目标是已知的，地高辛的 PK 和药效学 (PD) 尚未在成人中进行研究患有 SVD 的婴儿。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，而地高辛靶标婴儿心肌细胞在结构、代谢和不成熟和 SVD 导致功能改变。尽管尚未完全理解，但这些相互作用可能会影响地高辛的功效是通过不同的暴露、反应或两者来实现的。了解个体发育和疾病的关系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育提供信息至关重要治疗 SVD 婴儿的新型心力衰竭药物。尽管高