|Strategy, Management and Health Policy|
|Enabling Technology, Genomics, Proteomics||Preclinical Research||Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics||Clinical Development Phases I-III Regulatory, Quality, Manufacturing||Postmarketing 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.