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.

项目总结/摘要 钆基对比剂已广泛应用于临床磁共振成像 影像学研究然而，尽管它们有着卓越的安全声誉， 在过去的几年里，随着研究的深入， 证明了钆（Gd）的释放和随后在骨组织中的沉积， 肾功能正常和血脑屏障完整的患者的大脑。唯一可行的 减少钆沉积的健康后果的疗法是用螯合剂治疗， 试剂，形成可排泄的复合物，虽然钆，像其他重金属， 最难处理的元素在过去的三十年里，劳伦斯 伯克利国家实验室致力于一项研究计划，以发展口腔 用于锕系元素脱钙的治疗剂，导致活性药物 成分3，4，3-LI（1，2-HOPO）作为锕系元素螯合的特殊候选物。最初 由于平民需要对核威胁采取暴露后医疗对策， 3，4，3-LI（1，2-HOPO）的开发遵循了一个参考动物规则的程序 美国食品和药物管理局建立的批准路径，并专注于预 临床药理学和毒理学、制剂优化以及 去除注入的威胁放射性同位素（钚、镅、铥、铀或 镎）。此外，3，4，3-LI（1，2-HOPO）的口服制剂使其成为第一种口服和口服给药制剂。 毫无疑问是最有效的治疗性锕系元素去除产品。试验用 该制剂于2014年8月获得新药（IND，112，264）状态。然而，在这方面， 虽然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排异效果，最近 溶液热力学研究已经证实了其对其它F元素的极高亲和力， 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去离子剂，其可在给药前、给药期间或给药后使用 钆基造影剂。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的疗效特征 或用于防止沉积，而不改变造影剂用于成像的效力。的 通过此程序收集的数据将受益于已添加到数据体中的数据 可用于IND批准的产品，这可能导致适应症扩大， 在不久的将来临床研究和使用的前景。