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

 描述（由申请方提供）：Capture Pharmaceuticals，Inc.正在开发一种名为C2 E2的药物，最初用于治疗在核恐怖事件后被放射性锕系元素污染的人。由于锕系元素和镧系元素之间的相似性，预计C2 E2也将有效清除在磁共振成像（MRI）程序中给予Gd基造影剂（GBCA）后存在Gd残留组织负荷的患者的钆（Gd，一种镧系元素）。从GBCA释放的游离Gd 3+离子（其是有毒的）与肾源性系统性纤维化（NSF）和其他毒性有关。FDA随后在FDA批准的GBCA上放置了“黑框”警告。据信，释放的Gd 3+的毒性作用仅限于某些类别的GBCA和患有肾衰竭的患者。然而，最近的研究表明，既往接受过GBCA治疗的髋关节置换患者骨中的Gd浓度大大升高，并且该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程序一部分的患者都可能从GBCA中释放游离Gd 3+，并有发生Gd毒性的风险。本I期STTR申请中提出的工作包括体外研究，以确定结合人血浆中游离Gd 3+离子所需的C2 E2浓度，并计算C2 E2与Gd的亲和力结合常数。这些研究将使用我们以前建立的方法进行。还将通过使用ICP-MS测量采集样本中的Gd，评估口服C2 E2在GBCA前给药时预防Gd在骨中沉积以及在GBCA后给药时降低骨中Gd含量的能力。还将使用放射性测量和WinNonlin软件确定口服C2 E2的药代动力学以及绝对生物利用度。由于DTPA的前药类似物C2 E2可以口服给药，因此它在高Gd身体负荷患者和不希望重复注射的儿科患者中长期使用具有显著优势。C2 E2已经进行了广泛的GLP毒性测试，并与FDA举行了IND前会议，作为评估其人体安全性的第一步。该项目的里程碑是确定结合人血浆中90%游离Gd 3+离子所需的C2 E2浓度，确定Gd-C2 E2复合物的形成常数，确定预防或清除给药动物与对照动物骨和肝脏中统计学显著量Gd所需的C2 E2剂量，并测定C2 E2及其代谢物的药代动力学参数（吸收和消除常数、分布容积和绝对生物利用度）。本工作以及先前C2 E2工作（CMC、方法验证、GLP安全性/药理学/毒性研究等）的所有数据将被分析并组装在IND包中，准备提交给FDA。

 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.