Formulation and pharmacokinetics of subcutaneous administration of deferiprone for prevention of chronic heart failure following hemorrhagic myocardial infarction.

皮下注射去铁酮预防出血性心肌梗死后慢性心力衰竭的配方和药代动力学。

• 批准号: 10700370
• 负责人: Robert E Finney
• 金额: $ 39万
• 依托单位: CARDIO-THERANOSTICS LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10700370
• 关键词: Acceleration; Anatomy; Animal Model; Animals; Award; Biological Availability; Blood; Bypass; Canis familiaris; Cardiovascular system; Cause of Death; Cessation of life; Chelating Agents; Communication; Congestive Heart Failure; Data; Deferoxamine; Deposition; Development; Disease; Disease Progression; Dose; Drug Kinetics; Drug Stability; Environment; Excision; Exposure to; FDA approved; Fasting; Fatty acid glycerol esters; Formulation; Glucuronides; Goals; Half-Life; Hemorrhage; High Pressure Liquid Chromatography; Hour; Indiana; Infarction; Inflammation; Infusion Pumps; Insulin; Intravenous; Intravenous Bolus; Iron; Iron Chelation; Iron Overload; Legal patent; Life Expectancy; Liver; Macrophage; Metabolism; Methods; Myocardial Infarction; Nature; Oral; Patients; Pharmaceutical Preparations; Phase; Prevention; Publishing; Quality of life; Recovery of Function; Research; Risk; Route; Safety; Small Business Innovation Research Grant; Societies; Source; Staging; Supervision; Thalassemia; Universities; Washington; diabetic patient; heart function; improved; intravenous administration; liquid chromatography mass spectrometry; mortality; myocardial infarct sizing; novel therapeutics; recruit; side effect; subcutaneous; success; theranostics; type I diabetic

Problem: Approximately 50% of myocardial infarction (MI) patients progress to chronic heart failure (CHF) post-MI with a 5-year mortality rate of ~50% (>300,000 US deaths annually). Recent studies have elucidated an obligate mechanism for progression to CHF and new therapeutic opportunities. The data indicate: 1) that hemorrhage is associated with larger MIs; 2) when normalized for infarct size, patients with hemorrhagic MIs (hMIs) are at greater risk for CHF; and 3) intramyocardial iron from hemorrhage persists for years and drives persistent macrophage recruitment, inflammation, fat deposition, and loss of heart function. Extensive data demonstrate that deferiprone (a generic iron chelator FDA approved for iron overload in thalassemia patients) renders iron functionally inert, suppresses fat deposition, reduces iron within hMI territories, and supports anatomical and functional recovery away from CHF in a large animal model of hMI. Yet, deferiprone has an exceptionally short half-life (1-2 hours). Even given 2- to 3-times daily, large gaps in blood levels (exposure) of deferiprone are evident, with implications for gaps in suppression of disease progression and iron removal. Also, deferiprone has low bioavailability due to ~70% first-pass metabolism in the liver to the inactive 3-O- glucuronide metabolite, which may be associated with at least some (possibly most?) side effects. Solution: We propose that subcutaneous delivery of deferiprone using an infusion pump will provide continuous blood exposure to maintain iron in its inert state, will enable continuous iron removal, and will bypass first pass metabolism and minimize exposure to deferiprone’s primary metabolite. We further propose that a lower dose of deferiprone will prove highly efficacious. In Phase I SBIR studies, we will attain proof of concept that subcutaneous (SC) administration of deferiprone is efficient for delivery of deferiprone while avoiding first-pass metabolism. In Phase II SBIR studies, we will evaluate administration using as infusion pump, we will determine the minimum dose for maximal efficacy, and we will attain initial safety data. Aim 1: We will prepare deferiprone from available API sources for subcutaneous delivery using established methods for optimal patient comfort and compliance. Purity of the API, oral, IV, and SC drug will be verified using published HPLC methods and we will perform preliminary 1-month drug stability at ambient and accelerated storage conditions. Aim 2: We will establish LC/MS methods to quantitate and identify deferiprone and its metabolites and perform pharmacokinetic analysis of SC administration as compared to IV and oral delivery. We anticipate >90% bioavailability of SC deferiprone (compared to IV), no first-pass metabolism, and dose- linearity following SC administration. Impact: Foremost, this study holds the promise to be the first drug capable of removing an obligate driver of CHF in post hMI patients. The product further holds the promise to reduce side-effects, maintain more patients on therapy, and ultimately enhance quality of life and life expectancy of hundreds of thousands of post-hMI patients each year.

问题：大约50％的心肌梗塞（MI）患者发展为慢性心力衰竭（CHF） MI后5年死亡率约50％（> 300,000美国死亡）。最近的研究阐明了 向CHF发展和新的治疗机会的强制性机制。指示：1） 出血与更大的MIS有关； 2）当基础设施规模归一化时，出血失调的患者 （HMI）面临更大的CHF风险； 3）多年来，出血性心脏内铁持续多年 持续的巨噬细胞募集，影响，脂肪沉积和心脏功能的丧失。广泛的数据 证明证明有缺陷的（批准在Thalassya患者中获得铁超负荷的通用铁螯合剂FDA） 使铁在功能上惰性，抑制脂肪沉积，减少HMI领土内的铁并支撑 在大型HMI动物模型中，解剖学和功能恢复从CHF中恢复。然而，脱脂酮有一个 半衰期（1-2小时）异常短。即使每天2到3次，血液水平（暴露）的差距很大 脱氟酮是证据，对抑制疾病进展和去除铁的差异有影响。 同样，由于肝脏中〜70％的第一通途中代谢，脱脂酮具有较低的生物利用度 葡萄糖醛酸代谢物，可能至少与某些（可能是最可能？）副作用有关。解决方案： 我们建议使用输液泵的皮下递送失败的人会提供连续的血液 暴露于保持惰性状态的铁，将持续去除铁，并将绕过第一次过去 代谢，并最大程度地减少对脱发的原代代谢产物的接触。我们进一步建议较低的剂量 延期脱纤酮的效率将非常有效。在第一阶段的SBIR研究中，我们将获得概念证明 皮下（SC）失败的管理是有效的，可以在避免首次通道的同时提供失败的iprone 代谢。在第二阶段SBIR研究中，我们将评估使用AS Infusion Pump的管理，我们将 确定最大效率的最低剂量，我们将获得初始安全数据。目标1：我们会 使用已建立的方法从可用的API源中准备definerprone 最佳的患者舒适性和合规性。将使用API​​，口服，IV和SC药物的纯度进行验证 已发表的HPLC方法，我们将在环境中执行初步的1个月药物稳定性并加速 存储条件。目的2：我们将建立LC/MS方法来定量和识别脱佛酮及其ITS 与IV和口服分娩相比，代谢物并对SC给药进行药代动力学分析。 我们预计SC有缺陷的生物利用度> 90％（与IV相比），没有第一通代谢和剂量 - SC给药后线性。影响：最重要的是，本研究承诺成为第一种药物 能够在后HMI患者中删除CHF的义务司机。该产品进一步承诺 降低副作用，维持更多的患者治疗，并最终提高生活质量和生活质量 每年数十万HMI后患者的预期。