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%的心肌梗死（MI）患者进展为慢性心力衰竭（CHF） MI后，5年死亡率约为50%（美国每年死亡人数> 300，000）。最近的研究表明， CHF进展的专性机制和新的治疗机会。数据显示：（1） 出血与较大的MI相关; 2）当梗死面积标准化时，出血性MI患者 （hMI）CHF的风险更大; 3）出血引起的心肌内铁持续多年， 持续巨噬细胞募集、炎症、脂肪沉积和心脏功能丧失。广泛的数据 证明去铁酮（FDA批准用于地中海贫血患者铁超载的通用铁螯合剂） 使铁功能惰性，抑制脂肪沉积，减少hMI区域内的铁，并支持 在hMI的大型动物模型中远离CHF的解剖和功能恢复。然而，去铁酮具有 半衰期非常短（1 - 2小时）。即使每天给药2 - 3次， 去铁酮是明显的，与抑制疾病进展和铁去除的差距的影响。 此外，去铁酮的生物利用度低，因为在肝脏中约70%的首过代谢为无活性的3-O-去铁酮。 葡萄糖醛酸代谢物，可能与至少一些（可能是大多数？）副作用.解决方法： 我们建议使用输液泵皮下注射去铁酮将提供持续的血液 暴露，以保持铁在其惰性状态，将使连续的铁去除，并将绕过第一道 代谢和最大限度地减少暴露于去铁酮的主要代谢产物。我们进一步建议， 去铁酮会非常有效在第一阶段SBIR研究中，我们将获得概念证明， 去铁酮的皮下（SC）给药对于去铁酮的递送是有效的，同时避免首过 新陈代谢.在II期SBIR研究中，我们将评估使用输注泵的给药情况，我们将 确定最大疗效的最小剂量，我们将获得初步的安全性数据。目标1：我们将 使用已建立的方法从可获得的API来源制备用于皮下递送的去铁酮， 最佳的患者舒适度和依从性。API、口服、IV和SC药物的纯度将使用 已发表的HPLC方法，我们将在环境和加速条件下进行初步的1个月药物稳定性研究 储存条件目的二：建立去铁酮及其衍生物的LC/MS定量分析方法 代谢物的浓度，并进行SC给药与IV和口服给药相比的药代动力学分析。 我们预计SC去铁酮的生物利用度> 90%（与IV相比），无首过代谢，剂量- SC给药后的线性。影响：最重要的是，这项研究有望成为第一种药物 能够去除hMI后患者中CHF的专性驱动因素。该产品还承诺， 减少副作用，维持更多的患者接受治疗，最终提高生活质量和生活质量 每年有成千上万的hMI患者。