Novel decorporation agents are being developed to protect against radiological accidents and terrorists attacks. Radioactive americium is a significant component of nuclear fallout. Removal of large radioactive materials, such as 241Am, from exposed persons is a subject of significant interest due to the hazards they pose. The objective of this study was to evaluate the dose-related efficacy of daily doses of NanoDTPA™ Capsules for decorporating Am administered intravenously as a soluble citrate complex to male and female beagle dogs. In addition, the efficacy of the NanoDTPA™ Capsules for decorporating 241Am was directly compared to intravenously administered saline and DTPA. Animals received a single IV administration of 241Am(III)-citrate on Day 0. One day after radionuclide administration, one of four different doses of NanoDTPA™ Capsules [1, 2, or 6 capsules d(-1) (30 mg, 60 mg, or 180 mg DTPA) or 2 capsules BID], IV Zn-DTPA (5 mg kg(-1) pentetate zinc trisodium) as a positive control, or IV saline as a placebo were administered. NanoDTPA™ Capsules, IV Zn-DTPA, or IV saline was administered on study days 1-14. Animals were euthanized on day 21. A full necropsy was conducted, and liver, spleen, kidneys, lungs and trachea, tracheobronchial lymph nodes (TBLN), muscle samples (right and left quadriceps), gastrointestinal (GI) tract (stomach plus esophagus, upper and lower intestine), gonads, two femurs, lumbar vertebrae (L1-L4), and all other soft tissue remains were collected. Urinary and fecal excretion profiles were increased approximately 10-fold compared to those for untreated animals. Tissue contents were decreased compared to untreated controls. In particular, liver content was decreased by approximately eightfold compared to untreated animals. The results from this study further demonstrate that oral NanoDTPA™ Capsules are equally efficient compared to IV Zn-DTPA in decorporation of actinides.

Strategy, Management and Health PolicyEnabling Technology, Genomics, ProteomicsPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I‐III Regulatory, Quality, ManufacturingPostmarketing Phase IV Accidental or deliberate release of plutonium (Pu) and americium (Am) into the environment could lead to internal contamination by dermal exposure, ingestion, or inhalation and result in severe health risks to the exposed human population. Therefore, it is extremely important to develop chelation or decorporation therapies to remove these actinides from the exposed human population and thereby mitigate the deleterious effects of these actinides. Of the several chelating agents available, administration of intravenous (IV) injection of calcium (Ca) or zinc (Zn) diethylenetriaminepentaacetic (DTPA) immediately after exposure is well known to enhance the excretion of incorporated actinides. However, in emergency situations that require treating a large population, oral administration of either Zn‐DTPA or Ca‐DTPA would be the simplest treatment. A novel oral formulation of DTPA, NanoDTPA™ capsules was investigated for its toxicological and pharmacological profiles in dogs. No toxicity was observed in the dogs and the no observable adverse effect level was determined to be 350–700 mg NanoDTPA™ per dog or approximately 36.5–72.9 mg/kg NanoDTPA™. In the pharmacokinetic study, DTPA concentration from all dogs that were administered enteric‐coated NanoDTPA capsules was observed in the 1.5 and 2 h samples of the 30 and 60 mg/kg dosing arms, respectively. The highest mean DTPA plasma concentration was 3.04 ± 1.10 μg/ml and 4.82 ± 1.76 μg/ml at 3.0 and 2.8 h for the 30 and 60 mg/kg dosing arms, respectively. Additionally, the preliminary decorporation studies in rats exposed to 241 Am at a single dose (1 μCi) demonstrated that the NanoDTPA capsules at 60 mg/kg NanoDTPA were substantially equivalent to IV Zn‐DTPA administrated at 15 mg/kg DTPA, which is the highest dose available for the currently licensed product. These results demonstrate that oral NanoDTPA™ capsules are safe and capable of decorporation of actinides. The data from additional GLP studies linked to pharmacokinetic data in humans will be used to establish efficacy for regulatory submissions.