Exploring the use of a hydroxypyridinone decorporation agent for the removal of toxic residual gadolinium from MRI contrast agent administration

探索使用羟基吡啶酮脱色剂去除 MRI 造影剂给药中有毒残留的钆

• 批准号: 9387827
• 负责人: Rebecca J Abergel
• 金额: $ 26.3万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387827
• 关键词: Actinoid Series Elements; Address; Affinity; Animal Model; Animals; Biodistribution; Blood - brain barrier anatomy; Bone Tissue; Brain; Chelating Agents; Chelation Therapy; Clinical; Clinical Pharmacology; Clinical Research; Complex; Contrast Media; Data; Deposition; Development; Dose; Elements; Ensure; Excision; Excretory function; Fluoride Ion; Fluorine; Formulation; Future; Gadolinium; Goals; Health; Heavy Metals; Human; Image; Injectable; Inorganic Chemistry; Investigational Drugs; Laboratories; Lead; Ligands; Magnetic Resonance Imaging; Medical; Metabolism; Metals; Modeling; Mus; Neptunium; Nuclear; Oral; Patient Agents; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Plutonium; Program Development; Prophylactic treatment; Radioactive; Radiobiology; Radioisotopes; Radiolabeled; Regimen; Renal function; Research; Research Project Grants; Residual state; Safety; Series; Spectrum Analysis; Testing; Therapeutic; Thermodynamics; Tissues; Toxic effect; United States Food and Drug Administration; Uranium; absorption; animal rule; base; clinical toxicology; design; imaging agent; imaging study; in vivo; mouse model; pre-clinical; preclinical development; prevent; programs; prophylactic

Project Summary/Abstract Gadolinium-based contrast agents have been widely used in clinical magnetic resonance imaging studies. However, despite their exceptional safety reputation, serious toxicity issues associated with the use of these agents have emerged in the last several years, with studies demonstrating the release of gadolinium (Gd) and subsequent deposition in bone tissue and in the brain in patients with normal renal function and intact blood-brain barriers. The only practical therapy to reduce the health consequences of gadolinium deposition is treatment with chelating agents that form excretable complexes, although gadolinium, like other heavy metals, is among the most intractable elements to decorporate. Over the past three decades, the Lawrence Berkeley National Laboratory has dedicated a research program to the development of oral therapeutics for actinide decorporation, leading to the emergence of the active pharmaceutical ingredient 3,4,3-LI(1,2-HOPO) as an exceptional candidate for actinide sequestration. Initially driven by the civilian need for post-exposure medical countermeasures against nuclear threats, the development of 3,4,3-LI(1,2-HOPO) followed a program that references the Animal Rule approval path established by the U.S. Food and Drug Administration, and focused on pre- clinical pharmacology and toxicology, formulation optimization, as well as controlled efficacy for the removal of injected threat radioisotopes (plutonium, americium, curium, uranium or neptunium). In addition, the oral formulation of 3,4,3-LI(1,2-HOPO) makes it the first oral and indisputably most efficacious therapeutic actinide decorporation product. The Investigational New Drug (IND, 112,264) status was obtained in August 2014 for this drug product. However, while the preclinical development program has focused on demonstrating the outstanding decorporation efficacy of 3,4,3-LI(1,2-HOPO) in vivo for radioactive actinides exclusively, recent solution thermodynamic studies have confirmed its extremely high affinity for other f-elements, including Gd. In the proposed research project, we will explore the potential 3,4,3-LI(1,2-HOPO) as a Gd decorporation agent that may be used in anticipation of, during, or after administration of Gd-based contrast agents. Animal studies using established models will be performed to adequately characterize the efficacy profile of 3,4,3-LI(1,2-HOPO) for eliminating deposited Gd or for preventing deposition, without altering the potency of the contrast agent for imaging. The data gathered through this program will benefit from and be added to the body of data already available for the IND-approved product, which may then lead to an enlarged indication and prospects of clinical studies and use in the very near future.

项目概要/摘要 钆基造影剂已广泛应用于临床磁共振 影像学研究。然而，尽管它们具有卓越的安全声誉，但仍存在严重的毒性问题 过去几年出现了与这些药物的使用相关的研究 证明钆 (Gd) 的释放以及随后在骨组织和体内的沉积 肾功能正常且血脑屏障完整的患者的大脑。唯一实用的 减少钆沉积对健康影响的治疗方法是螯合治疗 形成可排泄复合物的物质，尽管钆和其他重金属一样，也是其中之一 最难装饰的元素。在过去的三十年里，劳伦斯 伯克利国家实验室专门开展了一项研究计划来开发口腔 锕系元素修饰疗法，导致活性药物的出现 成分 3,4,3-LI(1,2-HOPO) 是锕系元素螯合的特殊候选者。最初 由于民间需要针对核威胁采取暴露后医疗对策， 3,4,3-LI(1,2-HOPO) 的开发遵循参考动物规则的程序 美国食品和药物管理局制定的审批路径，重点是预审 临床药理学和毒理学、制剂优化以及疗效控制 消除注入的威胁放射性同位素（钚、镅、锔、铀或 镎）。此外，3,4,3-LI(1,2-HOPO)的口服制剂使其成为第一个口服和 毫无疑问是最有效的治疗性锕系元素修饰产品。调查性的 该药品于 2014 年 8 月获得新药 (IND, 112,264) 状态。然而， 而临床前开发计划的重点是展示杰出的 3,4,3-LI(1,2-HOPO)在体内对放射性锕系元素的唯一修饰效果，最近 溶液热力学研究已证实其与其他 f 元素具有极高的亲和力， 包括Gd。在拟议的研究项目中，我们将探索潜在的3,4,3-LI(1,2-HOPO) 作为 Gd 修饰剂，可在给药前、给药期间或给药后使用 Gd 基造影剂。将使用已建立的模型进行动物研究 充分表征 3,4,3-LI(1,2-HOPO) 消除沉积 Gd 的功效 或用于防止沉积，而不改变造影剂的成像效力。这 通过该计划收集的数据将受益于并添加到已经存在的数据体中 可用于 IND 批准的产品，这可能会导致适应症扩大， 近期临床研究和使用的前景。