Funding support: National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH); Grant number: RAI087604Z.
Significance of Single Variables in Defining Adequate Animal Models to Assess the Efficacy of New Radionuclide Decorporation Agents: Using the Contamination Dose as an Example
Article first published online: 13 AUG 2012
© 2012 Wiley Periodicals, Inc.
Drug Development Research
Special Issue: Radiation Drugs: A Hot Topic. An Update on Radiological Countermeasures Following the Fukushima Daiichi Nuclear Disaster
Volume 73, Issue 5, pages 281–289, August 2012
How to Cite
Jarvis, E. E., An, D. D., Kullgren, B. and Abergel, R. J. (2012), Significance of Single Variables in Defining Adequate Animal Models to Assess the Efficacy of New Radionuclide Decorporation Agents: Using the Contamination Dose as an Example. Drug Dev. Res., 73: 281–289. doi: 10.1002/ddr.21020
- Issue published online: 13 AUG 2012
- Article first published online: 13 AUG 2012
- National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). Grant Number: RAI087604Z
- internal contamination;
- nuclear medical countermeasure;
- chelation therapy
|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|
Internal radioactive contamination can arise in different ways, from accidents affecting nuclear sites and industrial or medical sources, to the possible terrorist use of radiological dispersal devices. In all cases, internalized radionuclides may pose significant health risks and must be removed from the body. The need for safe, practical, and efficacious actinide chelation therapy options has motivated the current preclinical development of new hydroxypyridinone-based actinide decorporation agents. In order to seek regulatory approval for such new decorporation agents, a number of efficacy studies must be performed and, in principle, must respond to selective criteria of the Animal Efficacy Rule from the US Food and Drug Administration (FDA). While many in vivo decorporation efficacy studies have been conducted over the past few decades using different animal species and contamination procedures, there is no designated standard animal model for the evaluation of new actinide chelation drugs. This study aims at probing the influence of a single variable such as the contamination dose on the efficacy of the chelators 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO) at removing plutonium-238 administered as a soluble citrate complex. The dependence of body burden on contamination dose observed in untreated animals was reduced with the hydroxypyridinonate chelators, more so than with the commercially available diethylenetriaminepentaacetic acid chelator. This study demonstrates how a slight change in the design of decorporation experiments can remarkably impact the efficacy profile of the tested drug, and thus the path a sponsor might take to gain FDA approval.