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

DESCRIPTION provided by applicant Capture Pharmaceuticals Inc is developing a drug called C E 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 C E 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 Gd ions which are toxic from GBCAs has been associated with Nephrogenic Systemic Fibrosis NSF and other toxicities The FDA subsequently placed andquot black boxandquot warnings on FDA approved GBCAs It was believed that the toxic effects of released Gd 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 Gd 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 C E concentration required to bind free Gd ions in human plasma and to calculate the affinity binding constant of C E for Gd These studies will be carried out using methods we have previously established The ability of orally administered C E 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 C E will also be established using radiometric measurements and WinNonlin software Because C E 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 C E 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 C E concentration required to bind of the free Gd ions in human plasma determination of the formation constant for the Gd C E complex identification of the C E 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 C E and its metabolites All of the data from this work as well as previous work with C E CMC method validations GLP safety pharmacology toxicity studies etc will be analyzed and assembled in an IND package ready for submission to the FDA PUBLIC HEALTH RELEVANCE The goal of this project is to test the ability of a new orally administered drug C E 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 C E will be included in a submission of an Investigational New Drug IND application to the Food and Drug Administration FDA