Prodrugs of DTPA as Radionuclide Decorporation Agents

The Ca and Zn complexes of Diethylenetriaminepenta-acetic acid (DTPA) have been shown to be effective in enhancing the elimination of transuranic elements such as americium (Am), plutonium (Pu) and curium (Cm) in individuals who have been contaminated with radioisotopes of these elements.  Injectable formulations of Ca-DTPA and Zn-DTPA are currently stored in the Strategic National Stockpile following accidental contamination or a nuclear terrorism event, e.g., the detonation of an Improvised Nuclear Device or Radiological Dispersal Device (‘dirty bomb’).  DTPA is a chelating agent that increases the rates of elimination of these elements through the exchange of calcium or zinc ions.  DTPA is very water-soluble but, unfortunately, its oral bioavailability is minimal (i.e., ~1%).  Thus, Ca- and Zn‐DTPA are classified as Class III compounds (high solubility; low permeability) under the Biopharmaceutical Classification System.  Because these products must be administered by a skilled professional and, like all sterile, injectable pharmaceuticals, are expensive to manufacture, they do not lend themselves well for use in an emergency situation.

In order to achieve higher oral bioavailability, we prepared lipophilic prodrugs of DTPA that serve to enhance the absorption of the chelator through the intestinal mucosal membrane. These prodrugs were designed to be metabolized to DTPA during or after absorption from the GI tract. We have demonstrated that our lead compound, designated as C2E5, has excellent decorporation efficacy in animals that have been contaminated with 241Am.  Our goal is to develop this prodrug into a drug product that can be included in the Strategic National Stockpile for use by the general public in the case of a radiation emergency.  While C2E5 appears to exhibit excellent radionuclide decorporation efficacy in animal models, it is a challenging molecule from a pharmaceutical development perspective.  It is a viscous oil that has resisted all attempts at crystallization, is relatively unstable in aqueous environments, possesses no chromophores and thus is difficult to analyze, has a complex metabolic profile and has an objectionable taste. Therefore, we are expending considerable effort to develop bioanalytical methods for C2E5 and suitable formulations that are palatable, stable, non-toxic and readily administered to adult and pediatric populations.

We are also conducting extensive animal experiments to determine its pharmacokinetic parameters, to study the mechanisms by which C2E5 is converted metabolized, and to establish the optimum dose and dosing schedule.  In addition, we are working with a number of small companies in NC on manufacturing issues, formal stability studies and GLP safety-toxicology studies in rodent and non-rodent models in preparation of an IND submission.  Finally, we are working with the Lovelace Respiratory Research Institute to test the efficacy of C2E5 in large animals that have been contaminated by inhalation of Am and Pu radioisotopes.  Ultimately, the C2E5 products will be advanced through the regulatory-based product development pathway under the “Animal Rule” (because true efficacy studies cannot ethically be conducted in humans) for approval by the FDA.

This project is supported by funding ($6.6 MM) from NIAID.  Collaborators on this project include Dr. Russ Mumper who is providing expertise in formulation and product development, and Dr. Bill Zamboni who directs GLP labs will be used for the bioassay work and who is writing the clinical study design and conducting the pharmacokinetic-toxicokinetic analyses.