An Interlaboratory Validation of the Radiation Dose Response Relationship (DRR) for H-ARS in the Rhesus Macaque

Abstract

The Medical Countermeasures against Radiological Threats (MCART) consortium has established a dose response relationship for the hematopoietic acute radiation syndrome (HARS) in the rhesus macaque conducted under an individualized supportive care protocol, including blood transfusions. Application of this animal model as a platform for demonstrating efficacy of candidate medical countermeasures is significantly strengthened when the model is independently validated at multiple institutions. The study reported here describes implementation of standard operating procedures at an institute outside the consortium in order to evaluate the ability to establish an equivalent radiation dose response relationship in a selected species. Validation of the animal model is a significant component for consideration of the model protocol as an FDA-recommended drug development tool in the context of the "Animal Rule." In the current study, 48 male rhesus macaques (4-8 kg) were exposed to total-body irradiation (TBI) using 6 MV photon energy at a dose rate of approximately 0.8 Gy min. Results show that onset and duration of the hematological response, including anemia, neutropenia, and thrombocytopenia, following TBI ranging from 6.25 to 8.75 Gy correlate well with previously reported findings. The lethality values at 60 d following TBI were estimated to be 6.88 Gy (LD30/60), 7.43 Gy (LD50/60), and 7.98 Gy (LD70/60). These values are equivalent to those published previously of 7.06 Gy (LD30/60), 7.52 Gy (LD50/60), and 7.99 Gy (LD70/60); the DRR slope (p = 0.68) and y-intercepts show agreement along the complete dose range for HARS. The ability to replicate the previously established institutional lethality profile (PROBIT) and model outcomes through careful implementation of defined procedures is a testament to the robustness of the model and highlights the need for consistency in procedures.

The Hematopoietic Syndrome of the Acute Radiation Syndrome in Rhesus Macaques

“…In this case, the desired clinical benefit is enhanced survival or prevention of major morbidity after exposure to potentially lethal doses of radiation across the hematopoietic acute radiation subsyndrome (USFDA 2014a). The non-human primate (NHP), rhesus macaque, is a relevant animal for the development of models that mimic the human response to the acute radiation syndrome (ARS) and the delayed effects of acute radiation exposure (DEARE) as well as treatment of the hematopoietic (H)-ARS, the gastrointestinal (GI)-ARS, immune reconstitution, prolonged GI damage, and delayed lung injury characteristic of the delayed effects DEARE (Monroy et al 1986;Gibbs et al 2007;Nikolich-Zugich 2007;MacVittie et al 2012aMacVittie et al and b, 2014MacVittie et al , 2015Farese et al 2012a;Herodin et al 2005;Messaoudi et al 2011;Garofalo et al 2014a and b;Hankey et al 2015;Thrall et al 2013Thrall et al , 2015. In this regard, the NHP, a well-characterized model, is a likely choice for defining the efficacy of MCM and conducting pivotal efficacy studies under the criteria of the FDA AR.…”

“…A recent inter-laboratory comparison has been reported using an exchange of standard operating procedures and medical management (Thrall et al 2015). A number of studies using rhesus macaques were performed decades ago without the use of medical management.…”

The MCART Consortium Animal Model Series

“…The database for the mouse is substantial and yet required considerable effort by respective MCART teams to establish valid DRRs for the H-, GI-ARS, and lung-DEARE A single study defined the H-ARS DRR plus medical management for the NHP ). MCART has recently collaborated with the team at SNBL to establish an equivalent NHP model of the H-ARS plus medical management (Thrall et al 2015). There has, however, never been a systematic review of the DRR for the H-ARS in the absence of medical management in the rhesus macaque.…”

“…All DRRs for the acute and delayed subsyndromes and MOI for NHP are based on this standardized delivery of dose. MCART-derived models can be validated by collaborative research sites using the same radiation physics-derived exposure protocols (Thrall et al 2015). The dose-and time-dependent organ-specific biology and the DRRs for all radiation sequelae are the result of uniform and consistent delivery of prescribed dose to the MLT target.…”

“…Validation of MCART models is accomplished through substantive use under variable conditions of MCM assessment as well as establishing an equivalent model at an extended and collaborative research site at SNBL (Shin Nippon Biomedical Laboratories, USA Ltd., Everett, WA, USA). MCART and SNBL research teams established a model at SNBL of the H-ARS in rhesus macaque, plus medical management under shared and equivalent standard operating procedures (Thrall et al 2015).…”