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) 患者会进展为慢性心力衰竭 (CHF) 心梗后 5 年死亡率约为 50%（美国每年死亡人数超过 300,000 人）。 进展为 CHF 的必然机制和新的治疗机会。数据表明：1) 出血与较大的心梗相关；2) 当梗塞面积标准化时，出血性心梗患者 (hMI) 发生 CHF 的风险更大；3) 出血引起的心肌内铁持续存在数年并驱动 持续的巨噬细胞募集、炎症、脂肪沉积和心脏功能丧失大量数据。 证明去铁酮（FDA 批准用于治疗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，减少人机界面内的铁，并支持 在大型 hMI 动物模型中，去铁酮可以使 CHF 的解剖学和功能恢复。 半衰期极短（1-2 小时），即使每天给药 2 至 3 次，血液浓度（暴露）差异也很大。 去铁酮的作用是显而易见的，对抑制疾病进展和除铁方面的差距具有影响。 此外，去铁酮的生物利用度较低，因为大约 70% 在肝脏中首过代谢为无活性的 3-O- 葡萄糖醛酸代谢物，可能与至少一些（可能是大多数？）副作用有关。 我们建议使用输液泵皮下输送去铁酮将提供连续的血液 暴露以保持铁处于惰性状态，将能够连续去除铁，并将绕过第一道工序 我们进一步建议降低剂量。 在第一阶段 SBIR 研究中，去铁酮将被证明非常有效。 皮下 (SC) 给予去铁酮可有效递送去铁酮，同时避免首过 在 II 期 SBIR 研究中，我们将评估使用输液泵的给药方式。 确定最大功效的最小剂量，我们将获得初步安全数据。 使用既定方法从可用的 API 来源制备去铁酮用于皮下递送 API、口服、静脉注射和皮下注射药物的最佳患者舒适度和依从性将通过使用进行验证。 已发布 HPLC 方法，我们将在环境和加速条件下进行初步 1 个月的药物稳定性测试 目标 2：我们将建立 LC/MS 方法来定量和鉴定去铁酮及其衍生物。 代谢物并进行 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，并且剂量- 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。 该产品能够消除 hMI 后患者 CHF 的必然驱动因素。 减少副作用，让更多患者接受治疗，最终提高生活质量和生活质量 每年有数十万 hMI 后患者的预期。