Lusutrombopag, an orally bioavailable, small molecule thrombopoietin receptor agonist, is approved for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure[1].
Lusutrombopag exhibits agonist activity for human thrombopoietin(TPO) receptor c-Mpl. Lusutrombopag promoted the proliferation of Ba/F3-hMpl cells. The 50% EC50 values of lusutrombopag Ba/F3-hMpl cells were 84.0, whereas lusutrombopag exhibited no proliferative activity in Ba/F3-mMpl cells. These results indicate that lusutrombopag promotes the proliferation of Ba/F3-hMpl cells via human c-Mpl. To investigate the signal transduction pathway of lusutrombopag, we evaluated the phosphorylation of JAK2, STAT3, STAT5 and p44/42 MAPK in Ba/F3-hMpl cells. Lusutrombopag phosphorylated these molecules similarly to rhTPO. These results suggest that lusutrombopag activates the same signal transduction pathways activated by rhTPO[2]
Lusutrombopag significantly increased circulating platelets in a dose-dependent manner during 21-day repeated oral administration in TPOR-Ki/Shi mice, was developed by replacing mouse Mpl with human-mouse chimera Mpl. Histopathological study of the TPOR-Ki/Shi mice on day 22 also revealed a significant increase in megakaryocytes in the bone marrow. These results indicate that lusutrombopag acts on human TPOR to upregulate differentiation and proliferation of megakaryocytic cells, leading to platelet production[2]
Lusutrombopag significantly increased the platelet count in all 31 patients with a mean increase of 31,000/μL.However, the increase in the platelet count after platelet transfusion was not statistically significant. When 13 patients repeated uses of lusutrombopag were counted platelet transfusion was not required in 82.1% (23/28) of treatments[3]
References:
[1]. Shirley M, McCafferty EH, et al. Lusutrombopag: A Review in Thrombocytopenia in Patients with Chronic Liver Disease Prior to a Scheduled Procedure. Drugs. 2019 Oct;79(15):1689-1695.
[2]. Yoshida H, Yamada H, et al. Development of a new knock-in mouse model and evaluation of pharmacological activities of lusutrombopag, a novel, nonpeptidyl small-molecule agonist of the human thrombopoietin receptor c-Mpl. Exp Hematol. 2018 Mar;59:30-39.e2.
[3]. Nomoto H, Morimoto N, et al. Lusutrombopag is effective and safe in patients with chronic liver disease and severe thrombocytopenia: a multicenter retrospective study. BMC Gastroenterol. 2020 Dec 14;20(1):427.
lusutrombopag 是一种具有口服生物利用度的小分子血小板生成素受体激动剂,已获准用于治疗计划接受手术的慢性肝病成年患者的血小板减少症[1]。
Lusutrombopag 对人血小板生成素 (TPO) 受体 c-Mpl 具有激动剂活性。 Lusutrombopag 促进 Ba/F3-hMpl 细胞的增殖。 lusutrombopag Ba/F3-hMpl 细胞的 50% EC50 值为 84.0,而 lusutrombopag 在 Ba/F3-mMpl 细胞中没有表现出增殖活性。这些结果表明 lusutrombopag 通过人 c-Mpl 促进 Ba/F3-hMpl 细胞的增殖。为了研究 lusutrombopag 的信号转导通路,我们评估了 Ba/F3-hMpl 细胞中 JAK2、STAT3、STAT5 和 p44/42 MAPK 的磷酸化。 Lusutrombopag 磷酸化这些分子类似于 rhTPO。这些结果表明,lusutrombopag 激活的信号转导通路与 rhTPO[2]
Lusutrombopag 在 TPOR-Ki/Shi 小鼠中重复口服给药 21 天期间以剂量依赖性方式显着增加循环血小板,该药物是通过用人-小鼠嵌合体 Mpl 替换小鼠 Mpl 而开发的。在第 22 天对 TPOR-Ki/Shi 小鼠进行的组织病理学研究也揭示了骨髓中巨核细胞的显着增加。这些结果表明,lusutrombopag 作用于人 TPOR,上调巨核细胞的分化和增殖,导致血小板生成[2]
Lusutrombopag 显着增加了所有 31 名患者的血小板计数,平均增加了 31,000/μL。但是,血小板输注后血小板计数的增加没有统计学意义。当对 13 名重复使用 lusutrombopag 的患者进行计数时,82.1% (23/28) 的治疗不需要血小板输注[3]