Romiplostim (Nplate®) as an effective radiation countermeasure to improve survival and platelet recovery in mice
Romiplostim (Nplate®) as an effective radiation countermeasure to improve survival and platelet recovery in mice
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DOI：
10.1080/09553002.2019.1605465
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发表时间：
2020-01-02
影响因子：
2.6
通讯作者：
Chang, Polly Y.
中科院分区：
文献类型：
--
作者：
Bunin, Deborah I.;Bakke, James;Chang, Polly Y.
目的：白细胞、血小板和网织红细胞的快速耗竭是急性放射综合征 (H-ARS) 造血损伤的标志，如果不及时治疗，可能会导致严重的健康后果，包括死亡。虽然粒细胞集落刺激因子 (G-CSF) 非格司亭 (Neupogen (R))、聚乙二醇非格司亭 (Neulasta (R)) 和沙格司亭 (Leukine (R)) 被批准可提高接受骨髓抑制剂量辐射的患者的生存率，但目前尚无医疗对策可用于治疗辐射暴露后也会导致的血小板减少症。 Romiplostim (Nplate (R)) 是一种血小板生成素受体激动剂，是 FDA 批准的第一个血小板生成刺激蛋白，用于治疗成人慢性免疫性血小板减少症的低血小板 (PLT) 计数。在此，我们介绍了 romiplostim 作为改善急性辐射后生存和 PLT 恢复的医学对策的小鼠分析结果。材料和方法：用 6.8 Gy X 射线对雄性和雌性 C57BL/6J 小鼠（11 - 12 周龄，n = 21/性别/组）进行全身照射 (TBI)，将 30 天存活率降低至 30% (LD70/30)。 TBI后24小时开始皮下施用媒介物、romiplostim和/或pegfilgrastim，持续1-5天。评估参数包括 30 天生存率、药代动力学和血液学。结果：单次 30 μg/kg 剂量的 romiplostim 后，实现了完全或最大疗效，存活率增加了 40%。较高剂量（100μg/kg）或更频繁剂量（每日3或5次剂量，30μg/kg）罗米司亭或与聚乙二醇非格司亭联合治疗未见进一步的生存获益。药效分析显示，与受辐射的对照动物相比，用 romiplostim 治疗的受辐射小鼠的血小板最低点没有那么低，并且恢复更快（第 8 天与第 10 天最低点；第 22 天与第 29 天恢复到接近基线）。注射罗米司亭后，血小板体积也增加得更快。 TBI romiplostim 治疗小鼠和对照小鼠之间其他血液学参数的动力学特征相似。 TBI 小鼠中 romiplostim 的血清峰值水平出现在注射后 4 - 24 小时 (T-max)，t(1/2) 与 24 小时相似。 30μg/kg+/-TBI后Cmax值类似于6ng/ml，300μg/kg后Cmax值类似于200ng/ml。罗米司亭剂量增加 10 倍，AUC（最后）值增加约 35 倍。结论：TBI 后 24 小时单次注射 romiplostim 是一种有前途的放射医学对策，无论有或没有聚乙二醇非格司亭，都能显着提高小鼠的生存率，并加速小鼠 PLT 恢复。
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.