Lusutrombopag (S-888711)

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.