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（由适用提供）：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被放射性actacinide元素污染的个体。由于肌动剂和灯笼之间的相似之处，预计C2E2也将有效地去除gd剂（GBCAS）作为磁共振成像（MRI）手术的一部分，在给药后具有GD残留的GD的患者中，GD残留的GD燃烧患者中，C2E2也将有效。 GBCA中有毒的游离GD3+离子的释放与肾脏基纤维化（NSF）和其他毒性有关。 FDA随后在FDA批准的GBCAS上发出了“黑匣子”警告。人们认为，释放的GD3+的毒性作用仅限于某些类别的GBCA和患有肾衰竭的患者。但是，最近已经证明，以前曾被施用GBCA的髋关节置换患者骨骼中GD的浓度大大升高，并且该观察结果与患者所接受的GBCA剂和肾功能状况无关。这是所有接受GBCA的患者作为MRI程序的一部分，可能会从GBCA释放免费的GD3+，并且有GD毒性的风险。在此阶段I STTR应用中提出的工作包括在体外研究，以确定结合人血浆中游离GD3+离子所需的C2E2浓度，并计算C2E2的亲和力结合常数对GD的亲和力结合常数。这些研究将使用我们先前已经建立的方法进行。在GBCA之前给药时，口服施用的C2E2能够防止GD沉积在骨骼中，并在GBCAS后施用时减少GD的骨骼含量，也将通过使用ICP-MS在收集的样品中测量GD来评估GD的骨骼含量。还将使用放射测量和Winnonlin软件建立口服C2E2的药代动力学以及口服C2E2的绝对生物利用度。因为C2E2是DTPA的前药类似物，可以口服给药，因此它在高GD身体伯元的患者和重复注射不良的儿科患者中具有长期使用的显着优势。 C2E2已经进行了广泛的GLP毒性测试，并与FDA举行了预先开会，以评估其在人类安全性的第一步。 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 C2E2及其代谢产物的常数，分布量和绝对生物利用度。该工作的所有数据以及先前使用C2E2（CMC，方法验证，GLP安全/药理学/毒性研究等）的工作将进行分析和组装，并在IND软件包中准备好提交给FDA。