Orally Bioavailable Gadolinium Chelators for Preventing and Ameliorating Toxicity Due to MRI Contrast Agents

口服生物可利用的钆螯合剂用于预防和改善 MRI 造影剂引起的毒性

• 批准号: 9044873
• 负责人: Michael Jay
• 金额: $ 20.56万
• 依托单位: CAPTURE PHARMACEUTICALS, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9044873
• 关键词: Acids; Actinoid Series Elements; Affinity; Animals; Binding; Bioavailable; Biological Availability; Body Burden; Boxing; Businesses; Chelating Agents; Chemistry; Chronic; Clinical Research; Collaborations; Complex; Computer software; Conduct Clinical Trials; Contrast Media; Control Groups; Cyclic GMP; Data; Deposition; Development; Dose; Drug Kinetics; Drug Packaging; Elements; Event; Excision; Excretory function; Fibrosis; Formulation; Gadolinium; Goals; Heavy Metals; High Pressure Liquid Chromatography; Human; Human Resources; Image; Imaging Techniques; In Vitro; Individual; Inductively Coupled Plasma Mass Spectrometry; Injection of therapeutic agent; Investigational Drugs; Investigational New Drug Application; Ions; Kidney; Kidney Failure; Lanthanoid Series Elements; Liver; Magnetic Resonance Imaging; Measurement; Measures; Metals; Methods; North Carolina; Nuclear; Oral; Patient Agents; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Plasma; Prevention; Prodrugs; Radioactive; Radioactive Elements; Radiolabeled; Renal function; Residual state; Risk; Safety; Sampling; Small Business Technology Transfer Research; Terrorism; Testing; Tissues; Toxic effect; Toxicity Tests; United States Food and Drug Administration; Universities; Validation; Work; absorption; analog; animal efficacy; base; bone; chelation; experience; gadolinium oxide; hip replacement arthroplasty; meetings; metal chelator; pediatric patients; prevent; public health relevance; radiotracer; treatment duration

 DESCRIPTION (provided by applicant): Capture Pharmaceuticals, Inc. is developing a drug called C2E2 initially intended for treatment of individuals who have been contaminated by radioactive actinide elements following a nuclear terrorism event. Because of the similarities between actinides and lanthanides, it is expected that C2E2 will also be effective in removing gadolinium (Gd, a lanthanide) in patients who have a residual tissue burden of Gd following the administration of Gd-Based Contrast Agents (GBCAs) as part of a magnetic resonance imaging (MRI) procedure. The release of free Gd3+ ions, which are toxic, from GBCAs has been associated with Nephrogenic Systemic Fibrosis (NSF) and other toxicities. The FDA subsequently placed "black box" warnings on FDA-approved GBCAs. It was believed that the toxic effects of released Gd3+ were restricted to certain classes of GBCAs and in patients suffering from renal failure. However, it has been more recently demonstrated that the concentrations of Gd in the bones of hip-replacement patients who had previously been administered a GBCA was greatly elevated, and that this observation was independent of the class of GBCA agent the patient had received and of their renal function status. Thus, all patients who receive a GBCA as part of an MRI procedure are likely to have free Gd3+ released from the GBCA and are at risk of experiencing Gd toxicity. The work proposed in this Phase I STTR application includes in vitro studies to determine the C2E2 concentration required to bind free Gd3+ ions in human plasma and to calculate the affinity binding constant of C2E2 for Gd. These studies will be carried out using methods we have previously established. The ability of orally administered C2E2 to prevent deposition of Gd in bone when administered prior to GBCAs and to reduce bone content of Gd when administered after GBCAs will also be assessed by measuring Gd in collected samples using ICP-MS. The pharmacokinetics as well as the absolute bioavailability of orally administered C2E2 will also be established using radiometric measurements and WinNonlin software. Because C2E2, a prodrug analog of DTPA, can be administered orally, it has significant advantages for long-term use in patients with high Gd body burdens and in pediatric patients where repeated injections are undesirable. C2E2 has already undergone extensive GLP toxicity testing and a pre-IND meeting was held with the FDA as a first step in assessing its safety in humans. The milestones of this project are the identification of the C2E2 concentration required to bind 90% of the free Gd3+ ions in human plasma, determination of the formation constant for the Gd-C2E2 complex, identification of the C2E2 doses necessary for prevention or removal of statistically significant amounts of Gd in bone and liver of treated animals vs. controls, and determination of the pharmacokinetic parameters (absorption and elimination constants, volume of distribution and absolute bioavailability) of C2E2 and its metabolites. All of the data from this work as well as previous work with C2E2 (CMC, method validations, GLP safety/pharmacology/toxicity studies, etc.) will be analyzed and assembled in an IND package ready for submission to the FDA.

 描述（由申请人提供）：Capture Pharmaceuticals, Inc.正在开发一种名为C2E2的药物，最初用于治疗核恐怖主义事件后受到放射性锕系元素污染的个体，由于锕系元素和镧系元素之间的相似性，预计会出现这种情况。对于服用基于 Gd 的药物后残留组织负荷为 Gd 的患者，C2E2 还可有效去除钆（Gd，一种镧系元素）造影剂 (GBCA) 作为磁共振成像 (MRI) 程序的一部分，GBCA 释放的有毒游离 Gd3+ 离子与肾源性系统性纤维化 (NSF) 和其他毒性有关。 FDA 批准的 GBCA 上出现“方框”警告。人们认为，释放的 Gd3+ 的毒性作用仅限于某些类别的 GBCA 以及患有肾功能衰竭的患者。然而，它已被最近的研究表明，先前接受 GBCA 治疗的髋关节置换患者的骨骼中 Gd 浓度大大升高，并且这一观察结果与患者接受的 GBCA 药物类别及其肾功能状态无关。因此，所有接受 GBCA 作为 MRI 手术一部分的患者都可能会从 GBCA 中释放出游离的 Gd3+，并且有发生 Gd 毒性的风险。本 I 期 STTR 申请中提出的工作包括确定 Gd3+ 的体外研究。结合人血浆中游离 Gd3+ 离子所需的 C2E2 浓度并计算 C2E2 对 Gd 的亲和力结合常数。在GBCA之前施用以及在GBCA之后施用时减少Gd的骨含量也将通过使用ICP-MS测量收集的样品中的Gd来评估药代动力学以及绝对生物利用度。口服 C2E2 的疗效也将使用放射测量和 WinNonlin 软件确定，因为 C2E2（DTPA 的前药类似物）可以口服给药，因此对于高 Gd 身体负荷的患者和儿童患者的长期使用具有显着的优势。 C2E2 已经进行了广泛的 GLP 毒性测试，并与 FDA 举行了预 IND 会议，作为评估其人体安全性的第一步。确定结合人血浆中 90% 游离 Gd3+ 离子所需的 C2E2 浓度，确定 Gd-C2E2 复合物的形成常数，确定预防或去除骨中统计显着量的 Gd 所需的 C2E2 剂量治疗动物与对照组的比较，以及 C2E2 及其代谢物的药代动力学参数（吸收和消除常数、分布体积和绝对生物利用度）的测定。工作以及之前的 C2E2 工作（CMC、方法验证、GLP 安全/药理学/毒性研究等）将被分析并组装在 IND 包中，准备提交给 FDA。