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

 描述(由申请人提供)：Capture PharmPharmticals，Inc.正在开发一种名为C2E2的药物，最初旨在治疗在核恐怖主义事件后受到放射性鳗系元素污染的个人。由于榄系元素和镧系元素之间的相似性，预计在磁共振成像(MRI)过程中使用基于Gd的造影剂(GBCA)后，对于组织中残留Gd的患者，C2E2也将有效地去除Gd(Gd，一种稀土元素)。Gd3+离子是有毒的，从GBCA中释放出来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“黑匣子”警告。据认为，Gd3+的毒性作用仅限于某些类型的GBCA和肾功能衰竭患者。然而，最近的研究表明，以前接受过GBCA的髋关节置换术患者骨骼中的Gd浓度显著升高，而且这种观察结果与患者接受的GBCA试剂的类别和他们的肾功能状态无关。因此，所有接受GBCA作为MRI程序的一部分的患者都可能从GBCA中释放出游离Gd3+，并面临经历Gd毒性的风险。这项在第一阶段STTR应用中提出的工作包括体外研究，以确定与人体血浆中游离Gd3+离子结合所需的C2E2浓度，并计算C2E2与Gd的亲和结合常数。这些研究将使用我们以前建立的方法进行。口服C2E2在GBCA之前给药时防止Gd在骨中沉积的能力，以及在GBCA后给药时减少Gd的骨含量的能力也将通过使用ICPMS测量收集的样本中的Gd来评估。口服C2E2的药代动力学以及绝对生物利用度也将通过放射测量和WinNonlin软件来确定。由于C2E2是DTPA的前体药物类似物，可以口服，因此对于高Gd身体负荷的患者和不希望重复注射的儿科患者来说，它具有长期使用的显著优势。C2E2已经接受了广泛的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与人体血浆中90%的游离Gd3+离子结合所需的C2E_2浓度，测定Gd-C_2E_2复合体的形成常数，确定与对照组相比，防止或消除治疗动物骨骼和肝脏中具有统计学意义的Gd所需的C_2E_2剂量，以及测定C_2E_2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)。这项工作以及之前的C2E2工作(CMC、方法验证、GLP安全性/药理学/毒性研究等)的所有数据。将被分析和组装在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.