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.
The goal of this project is to test the ability of a new, orally administered drug, C2E2, to enhance the excretion of a toxic material called gadolinium, a metal that is frequently used to enhance MRI images. The results of these studies as well as previous studies with C2E2 will be included in a submission of an Investigational New Drug (IND) application to the Food and Drug Administration (FDA).
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