The most common side effects include fatigue, nausea, hair loss (alopecia), constipation, certain nerve damage causing weakness or numbness in the hands and feet (peripheral neuropathy), abdominal pain and fever (pyrexia).[10] Eribulin may also cause low levels of infection-fighting white blood cells (neutropenia) or decreased levels of potassium or calcium.[10]
Eribulin was approved for medical use in the United States in November 2010,[11] the European Union in March 2011,[5] and Canada in December 2011.[2][12][13] It is available as a generic medication.[6]
Eribulin is indicated for the treatment of people with locally advanced or metastatic breast cancer,[5][14][15][16][17][18] and for the treatment of adults with unresectable liposarcoma.[5][10][19]
Serious side effects may include anaemia; decrease in white blood cell count, which can increase the risk of serious infections that could lead to death; hair loss; cancer-related fatigue; numbness, tingling or burning in the hands and feet (neuropathy); harm to a developing fetus; as well as changes in heartbeat (QTc prolongation), that may also lead to death.[10][20][unreliable medical source?]
Eribulin is a mechanistically unique inhibitor of microtubule dynamics,[25][26] binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules.[27][28]
Eribulin has both cytotoxic and non-cytotoxic mechanisms of action. Its cytotoxic effects are related to its antimitotic activities, wherein apoptosis of cancer cells is induced following prolonged and irreversible mitotic blockade.[29][30] In addition to its cytotoxic, antimitotic-based mechanisms, preclinical studies in human breast cancer models have shown that eribulin also exerts complex effects on the biology of surviving cancer cells and residual tumors that appear unrelated to its antimitotic effects. These non-mitotic mechanisms include vascular remodeling that leads to increased tumor perfusion and mitigation of tumor hypoxia, phenotypic changes consistent with reversal of epithelial-mesenchymal transition (EMT), and decreased capacity for migration and invasion leading to reduced metastatic capacity as measured in a preclinical experimental metastasis model.[31][32] In other studies, eribulin treatment of leiomyosarcoma and liposarcoma cells leads to increased expression of smooth muscle and adipocyte differentiation antigens, respectively.[33] Taxane-resistant cancers are often unresponsive to eribulin. A recent study found that this resistance is due to expression of multidrug resistance protein 1 (MDR1).[34] Fluorescently labeled eribulin has been used to study the pharmacokinetics and pharmacodynamics at single cell level in vivo.[34]
The synthesis of eribulin was first published[35] in 2001; a new synthetic route to the drug was published in 2009.[36]
Two eribulin based products are in the research and development phase; a liposomal formulation and antibody drug combination therapy, both are for the treatment of solid tumors. The liposomal formulation of eribulin, E7389 liposomal, is in Phase I clinical trials.[38] Preliminary in vivo experiments show a decrease in C(max) and a longer half-life with the liposomal formulation.[39] The drug antibody eribulin combination therapy is a joint venture between Eisai and Merck. The clinical trials combine eribulin and pembrolizumab, a PD-1 inhibitor, for the treatment of breast cancer and other advanced cancers.[40]
^Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, et al. (February 2001). "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B". Cancer Research. 61 (3): 1013–21. PMID11221827.
^Yu MJ, Kishi Y, Littlefield BA (2005). "Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B". In Newman DJ, Kingston DG, Cragg GM (eds.). Anticancer agents from natural products. Washington, DC: Taylor & Francis. ISBN978-0-8493-1863-4.[page needed]
^Wilson L, Lopus M, Miller HP, Azarenko O, Riffle S, Smith JA, et al. (October 2015). "Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the βIII tubulin isotype". Biochemistry. 54 (42): 6482–9. doi:10.1021/acs.biochem.5b00745. PMID26435331.
^Seletsky BM, Wang Y, Hawkins LD, Palme MH, Habgood GJ, DiPietro LV, et al. (November 2004). "Structurally simplified macrolactone analogues of halichondrin B". Bioorganic & Medicinal Chemistry Letters. 14 (22): 5547–50. doi:10.1016/j.bmcl.2004.08.068. PMID15482921.
^Kim DS, Dong CG, Kim JT, Guo H, Huang J, Tiseni PS, et al. (November 2009). "New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: double-inversion approach". Journal of the American Chemical Society. 131 (43): 15636–41. doi:10.1021/ja9058475. PMID19807076.
^Clinical trial number NCT03207672 for "Study of E7389 Liposomal Formulation in Subjects With Solid Tumor" at ClinicalTrials.gov
^Yu Y, Desjardins C, Saxton P, Lai G, Schuck E, Wong YN (February 2013). "Characterization of the pharmacokinetics of a liposomal formulation of eribulin mesylate (E7389) in mice". International Journal of Pharmaceutics. 443 (1–2): 9–16. doi:10.1016/j.ijpharm.2013.01.010. PMID23313921.
^Clinical trial number NCT03222856 for "Ph II Study of Pembrolizumab & Eribulin in Patients With HR+/HER2- MBC Previously Treated With Anthracyclines & Taxanes (KELLY)" at ClinicalTrials.gov
N
Y (what is this?) (verify)
This article incorporates text from this source, which is in the public domain.
