Romiplostim (Nplate (R)) As An Effective Radiation Countermeasure To Improve Survival And Platelet Recovery In Mice

Purpose: Rapid depletion of white blood cells, platelets, and reticulocytes are hallmarks of hematopoietic injury of acute radiation syndrome (H-ARS) and, if left untreated, can lead to severe health consequences including death. While the granulocyte colony stimulating factors (G-CSF) filgrastim (Neupogen (R)), pegfilgrastim (Neulasta (R)), and sargramostim (Leukine (R)) are approved to increase survival in patients exposed to a myelosuppressive dose of radiation, no medical countermeasure is currently available for treatment of the thrombocytopenia that also results following radiation exposure. Romiplostim (Nplate (R)), a thrombopoietin receptor agonist, is the first FDA-approved thrombopoiesis-stimulating protein for the treatment of low platelet (PLT) counts in adults with chronic immune thrombocytopenia. Herein, we present the results of an analysis in mice of romiplostim as a medical countermeasure to improve survival and PLT recovery following acute radiation. Materials and methods: Male and female C57BL/6J mice (11 - 12 weeks of age, n = 21/sex/group) were total body irradiated (TBI) with 6.8 Gy X-rays that reduces 30-day survival to 30% (LD70/30). Vehicle, romiplostim, and/or pegfilgrastim were administered subcutaneously beginning 24 h after TBI for 1-5 days. Evaluation parameters included 30-day survival, pharmacokinetics, and hematology. Results: Full or maximal efficacy with an similar to 40% increase in survival was achieved after a single 30 mu g/kg dose of romiplostim. No further survival benefit was seen with higher (100 mu g/kg) or more frequent dosing (3 or 5 once daily doses at 30 mu g/kg) of romiplostim or combined treatment with pegfilgrastim. Pharmacodynamic analysis revealed that the platelet nadir was not as low and recovery was faster in the irradiated mice treated with romiplostim when compared with irradiated control animals (Day 8 versus 10 nadir; Day 22 versus 29 recovery to near baseline). Platelet volume also increased more rapidly after romiplostim injection. Kinetic profiles of other hematology parameters were similar between TBI romiplostim-treated and control mice. Peak serum levels of romiplostim in TBI mice occurred 4 - 24 h (T-max) after injection with a t(1/2) of similar to 24 h. Cmax values were at similar to 6 ng/ml after 30 mu g/kg +/- TBI and similar to 200 ng/ml after 300 mu g/kg. A 10-fold higher romiplostim dose increased the AUC(last) values by similar to 35-fold. Conclusion: A single injection of romiplostim administered 24 h after TBI is a promising radiation medical countermeasure that dramatically increased survival, with or without pegfilgrastim, and hastened PLT recovery in mice.