Efficacy of delayed administration of sargramostim up to 120 hours post exposure in a nonhuman primate total body radiation model.

BACKGROUND: High dose ionizing radiation exposure is associated with myelo-depression leading to pancytopenia and the expected clinical manifestations of acute radiation syndrome (ARS). Herein, we evaluated the efficacy of sargramostim (Leukine®, yeast-derived rhu GM-CSF), with regimens delivered at 48, 72, 96, or 120 h after radiation exposure. METHODS: A randomized and blinded nonhuman primate (NHP) study was conducted to assess the effects of sargramostim treatment on ARS. NHPs were exposed to total body radiation (LD83/60 or lethal dose 83% by Day 60) and were randomized to groups receiving daily subcutaneous dosing of sargramostim starting from either 48, 72, 96, or 120 h post-irradiation. Additionally, separate groups receiving sargramostim treatment at 48 h post-irradiation also received prophylactic treatment with azithromycin. Sargramostim treatment of each animal continued until the preliminary absolute neutrophil count (ANC) returned to ≥1000/µL post-nadir for three consecutive days or the preliminary ANC exceeded 10,000/µL, which amounted to be an average of 15.95 days for all treatment groups. Prophylactic administration of enrofloxacin was included in the supportive care given to all animals in all groups. All animals were monitored for 60 days post-irradiation for mortality, hematological parameters, and sepsis. RESULTS: Delayed sargramostim treatment at 48 h post-irradiation significantly reduced mortality (p = .0032) and improved hematological parameters including neutrophil but also lymphocyte and platelet counts. Additional delays in sargramostim administration at 72, 96, and 120 h post-irradiation were also similarly effective at enhancing the recovery of lymphocyte, neutrophil, and platelet counts compared to control. Sargramostim treatment also improved the survival of the animals when administered at up to 96 h post-irradiation. While sargramostim treatment at 48 h significantly reduced mortality associated with sepsis (p ≤ .01), the additional prophylactic treatment with azithromycin did not have clinically significant effects. CONCLUSION: In a NHP ARS model, sargramostim administered starting at 48 h post-radiation was effective to improve survival, while beneficial hematological effects were observed with sargramostim initiated up to 120 h post exposure.

Pharmacodynamics of romiplostim alone and in combination with pegfilgrastim on acute radiation-induced thrombocytopenia and neutropenia in non-human primates.

Purpose: Evaluation of the pharmacodynamics (PD) and pharmacokinetics (PK) of romiplostim alone and in combination with pegfilgrastim in a non-human primate (NHP) model of acute radiation syndrome (ARS).Materials and methods: Male and female rhesus macaques were subjected to Cobalt-60 γ irradiation, at a dose of 550 cGy 24 h prior to subcutaneous administration of either romiplostim alone as a single (2.5 or 5.0 mg/kg on Day 1) or repeat dose (5.0 mg/kg on Days 1 and 8), pegfilgrastim alone as a repeat dose (0.3 µg/kg on Day 1 and 8), or a combination of both agents (romiplostim 5.0 mg/kg on Day 1; pegfilgrastim 0.3 µg/kg on Days 1 and 8). Clinical outcome, hematological parameters and PK were assessed throughout the 45 d study period post-irradiation.Results: Administration of romiplostim, pegfilgrastim or the combination of both resulted in significant improvements in hematological parameters, notably prevention of severe thrombocytopenia, compared with irradiated, vehicle control-treated NHPs. The largest hematologic benefit was observed when romiplostim and pegfilgrastim were administered as a combination therapy with much greater effects on both platelet and neutrophil recovery following irradiation compared to single agents alone.Conclusions: These results indicate that romiplostim alone or in combination with pegfilgrastim is effective at improving hematological parameters in an NHP model of ARS. This study supports further study of romiplostim as a medical countermeasure to improve primary hemostasis and survival in ARS.

Characterization of a partial-body irradiation model with oral cavity shielding in nonhuman primates.

Purpose: Characterization of a novel partial-body irradiation (PBI) shielding strategy in nonhuman primates (NHP; rhesus macaques), aimed at protecting the oral cavity, with respect to various gastrointestinal acute radiation syndrome (GI-ARS) syndrome parameters as well as buccal ulceration development.Materials and methods: NHPs were irradiated using a Cobalt-60 gamma source, in a single uniform dose, ranging from 9-13 Gy and delivered at 0.60-0.80 Gy min-1. Animals were either partially shielded via oral cavity shielding (PBIOS) or underwent total-body irradiation (TBI).Results: Clinical manifestations of GI-ARS, and also radiation-induced hematology and clinical chemistry changes, following PBIOS were comparable to the PBI NHP GI-ARS model utilizing shielding of the distal pelvic limbs and were significantly milder than TBI at similar radiation doses. Nadir citrulline levels were comparable between PBIOS and TBI but signs of recovery appeared earlier in PBIOS-treated animals. The PBIOS model prevented oral mucositis, whereas the TBI model presented buccal ulcerations at all tested radiation dose levels.Conclusions: Taken together, these results suggest that the PBIOS model is a suitable alternative to traditional PBI. For GI-ARS investigations requiring orally administered medical countermeasures, PBIOS confers added value due to the prevention of oral mucositis over traditional PBI.