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

问题：大约50%的心肌梗死患者进展为慢性心力衰竭(CHF) 心肌梗死后，5年死亡率约为50%(&gt；美国每年死亡30万人)。最近的研究阐明了 进展为充血性心力衰竭的专有机制和新的治疗机会。数据表明：1) 出血与较大的心肌梗死有关；2)当梗死面积归一化时，出血性心肌梗死患者 (HMI)患CHF的风险更大；以及3)出血引起的心肌内铁持续多年并导致 持续性巨噬细胞募集、炎症、脂肪沉积和心脏功能丧失。广泛的数据 证明去铁酮(一种FDA批准用于地中海贫血患者铁负荷过高的非专利铁络合剂) 使铁功能惰性，抑制脂肪沉积，减少HMI区域内的铁，并支持 HMI大型动物模型脱离CHF后的解剖和功能恢复。然而，去铁酮有一个 极短的半衰期(1-2小时)。即使每天服用2-3次，血液水平(暴露)也会有很大差距 去铁酮是明显的，与抑制疾病进展和铁清除方面的差距有关。 此外，去铁酮的生物利用度较低，因为~70%的肝脏首过代谢为非活性的3-O- 葡萄糖醛酸代谢物，它可能与至少一些(可能是大多数？)副作用。解决方案： 我们认为，使用输液泵皮下注射去铁酮将提供持续的血液。 接触以保持铁的惰性状态，将实现连续除铁，并将绕过第一次通过 新陈代谢，并最大限度地减少接触去铁酮的主要代谢物。我们进一步建议，较低的剂量 将被证明是非常有效的。在第一阶段SBIR研究中，我们将获得概念证明 皮下注射去铁酮在避免首次通过的同时是有效的 新陈代谢。在第二阶段SBIR研究中，我们将评估用作输液泵的给药情况，我们将 确定最大药效的最小剂量，即可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现有的原料药来源制备皮下给药用的去铁酮 最佳的患者舒适度和遵从性。原料药、口服、静脉和SC药物的纯度将使用以下方法进行验证 公布的高效液相色谱方法和我们将进行初步的1个月的药物稳定性在常压和加速 储存条件。目的2：建立去铁酮及其主要成分的LC/MS定量鉴定方法。 与静脉注射和口服给药相比，进行SC给药的药代动力学分析。 我们预计SC去铁酮的生物利用度为90%(与静脉注射相比)，没有首过代谢，剂量- SC管理后的线性。影响：最重要的是，这项研究承诺成为第一种药物 能够去除HMI后患者心力衰竭的专职驱动因素。该产品进一步保持了对 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 预计每年有数十万HMI后患者。

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.