Eribulin Explained

Verifiedfields:changed
Verifiedrevid:461094948
Width:300
Usan:eribulin mesylate
Jan:eribulin mesilate
Tradename:Halaven, Mevlyq
Dailymedid:Eribulin
Pregnancy Au:D
Pregnancy Au Comment:[1]
Routes Of Administration:Intravenous
Class:Antineoplastic agent
Atc Prefix:L01
Atc Suffix:XX41
Legal Au:S4
Legal Ca:Rx-only
Legal Uk:POM
Legal Uk Comment:[2]
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[3] [4] [5]
Legal Status:Rx-only[6] [7]
Cas Number:253128-41-5
Pubchem:11354606
Drugbank:DB08871
Chemspiderid:24721813
Unii:LR24G6354G
Kegg:D08914
Chebi:63587
Chembl:1683590
Synonyms:E7389, ER-086526, NSC-707389
Iupac Name:2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy- 7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2',3'-5,6) pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4H)-one
C:40
H:59
N:1
O:11
Smiles:CC1CC2CCC3C(=C)CC(O3)CCC45CC6C(O4)C7C(O6)C(O5)C8C(O7)CCC(O8)CC(=O)CC9C(CC(C1=C)O2)OC(C9OC)CC(CN)O
Stdinchi:1S/C40H59NO11/c1-19-11-24-5-7-28-20(2)12-26(45-28)9-10-40-17-33-36(51-40)37-38(50-33)39(52-40)35-29(49-37)8-6-25(47-35)13-22(42)14-27-31(16-30(46-24)21(19)3)48-32(34(27)44-4)15-23(43)18-41/h19,23-39,43H,2-3,5-18,41H2,1,4H3/t19-,23+,24+,25-,26+,27+,28+,29+,30-,31+,32-,33-,34-,35+,36+,37+,38-,39+,40+/m1/s1
Stdinchikey:UFNVPOGXISZXJD-JBQZKEIOSA-N

Eribulin, sold under the brand name Halaven among others, is an anti-cancer medication used to treat breast cancer and liposarcoma.[8]

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). Eribulin may also cause low levels of infection-fighting white blood cells (neutropenia) or decreased levels of potassium or calcium.

Eribulin was approved for medical use in the United States in November 2010,[9] the European Union in March 2011, and Canada in December 2011.[10] [11] [12] It is available as a generic medication.

Medical uses

Eribulin is indicated for the treatment of people with locally advanced or metastatic breast cancer,[13] [14] [15] [16] [17] and for the treatment of adults with unresectable liposarcoma.[18] [19]

Adverse effects

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.[20]

Structure and mechanism

Eribulin is a fully synthetic macrocyclic ketone analog of the marine natural product halichondrin B,[21] [22] the parent molecule being a naturally occurring, potent mitotic inhibitor with a unique mechanism of action. The parent molecule was originally found in the sponge Halichondria okadai.[23] [24]

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]

Research

Eribulin is being investigated for use in a variety of solid tumors, including breast cancer, non-small cell lung cancer, prostate cancer, brain cancer, cervical cancer, urothelial cancer, melanoma, solitary fibrous tumors, and various sarcomas.[37]

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. Preliminary in vivo experiments show a decrease in C(max) and a longer half-life with the liposomal formulation.[38] 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.

Notes and References

  1. Web site: Eribulin (Halaven) Use During Pregnancy . Drugs.com . 22 October 2019 . 9 July 2020.
  2. Web site: Halaven 0.44 mg/ml solution for injection . (emc) . 16 January 2023 . 16 December 2023.
  3. Web site: Halaven EPAR . European Medicines Agency (EMA) . 17 March 2011 . 16 December 2023.
  4. Web site: Mevlyq EPAR . European Medicines Agency (EMA) . 9 February 2024 . 19 February 2024.
  5. Web site: Mevlyq product information . Union Register of medicinal products . 13 February 2024 . 19 February 2024.
  6. Eisai Announces Japan Launch Of Anticancer Agent Halaven . Eisai Co., Ltd. . 19 July 2011 . 15 February 2021.
  7. Anticancer Agent Halaven Approved For Treatment Of Locally Advanced Or Metastatic Breast Cancer In China . Eisai Co., Ltd. . 17 July 2019 . 15 February 2021.
  8. Web site: Halaven- eribulin mesylate injection . DailyMed . 22 December 2017 . 9 July 2020.
  9. Web site: Drug Approval Package: Halaven (erbulin mesylate) NDA 201532 . U.S. Food and Drug Administration (FDA) . 9 July 2020.
  10. Web site: Halaven Product information . . 22 October 2009 . 16 December 2023.
  11. Web site: Halaven for Metastatic Breast Cancer . Canadian Agency for Drugs and Technologies in Health . 9 March 2015 . 9 July 2020.
  12. Eisai Announces Canadian Approval of its Anticancer Agent Halaven . Eisai Co., Ltd. . 9 July 2020.
  13. FDA approves new treatment option for late-stage breast cancer . U.S. Food and Drug Administration (FDA) . 15 November 2010 . 15 November 2010 . https://web.archive.org/web/20101117013510/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm233863.htm . 17 November 2010 . dead .
  14. Web site: Eribulin . U.S. Food and Drug Administration . 28 January 2016 . 16 December 2023.
  15. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/nd_ad_2012_halaven_141946-eng.php Notice of Decision for Halaven
  16. Web site: Halaven for Metastatic Breast Cancer . Canadian Agency for Drugs and Technologies in Health . 9 March 2015 . 9 July 2020.
  17. Eisai Announces Canadian Approval of its Anticancer Agent Halaven . Eisai Co., Ltd. . 9 July 2020.
  18. FDA approves first drug to show survival benefit in liposarcoma . U.S. Food and Drug Administration (FDA) . 28 January 2016 . 9 July 2020.
  19. U.S. FDA Approves Eisai's Anticancer Agent Halaven For The Treatment Of Advanced Liposarcoma . Eisai Co., Ltd. . 29 January 2016 . 15 February 2021.
  20. Web site: 5 June 2015 . Eribulin (Halaven) . 15 September 2022 . Breast Cancer Now .
  21. Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA . In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B . Cancer Research . 61 . 3 . 1013–21 . February 2001 . 11221827 .
  22. Book: Newman DJ, Kingston DG, Cragg GM . Anticancer agents from natural products . Taylor & Francis . Washington, DC . 2005 . Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B . Yu MJ, Kishi Y, Littlefield BA . Yoshito Kishi . 978-0-8493-1863-4 .
  23. Hirata Y, Uemura D . 1 January 1986. Halichondrins - antitumor polyether macrolides from a marine sponge. Pure and Applied Chemistry. 58. 5. 701–710. 10.1351/pac198658050701. 38138047 . 1365-3075. free . doi .
  24. Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E . Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data . The Journal of Biological Chemistry . 266 . 24 . 15882–9 . August 1991 . 10.1016/S0021-9258(18)98491-7 . 1874739 . free . doi .
  25. Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L . The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth . Molecular Cancer Therapeutics . 4 . 7 . 1086–95 . July 2005 . 16020666 . 10.1158/1535-7163.MCT-04-0345 . 38459382 . free . doi .
  26. Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA . Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase . Molecular Cancer Therapeutics . 7 . 7 . 2003–11 . July 2008 . 18645010 . 2562299 . 10.1158/1535-7163.MCT-08-0095 .
  27. Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, Jordan MA . Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability . Biochemistry . 49 . 6 . 1331–7 . February 2010 . 20030375 . 2846717 . 10.1021/bi901810u .
  28. Wilson L, Lopus M, Miller HP, Azarenko O, Riffle S, Smith JA, Jordan MA . Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the βIII tubulin isotype . Biochemistry . 54 . 42 . 6482–9 . October 2015 . 26435331 . 10.1021/acs.biochem.5b00745 .
  29. Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, Kishi Y, Yu MJ, Littlefield BA . Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389 . Cancer Research . 64 . 16 . 5760–6 . August 2004 . 15313917 . 10.1158/0008-5472.CAN-04-1169 . 30919443 . free . doi .
  30. Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, Zhu X, Lewis BM, Kishi Y, Yu MJ, Littlefield BA . Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions . Cancer Research . 71 . 2 . 496–505 . January 2011 . 21127197 . 10.1158/0008-5472.CAN-10-1874 . free . doi .
  31. Funahashi Y, Okamoto K, Adachi Y, Semba T, Uesugi M, Ozawa Y, Tohyama O, Uehara T, Kimura T, Watanabe H, Asano M, Kawano S, Tizon X, McCracken PJ, Matsui J, Aoshima K, Nomoto K, Oda Y . Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models . Cancer Science . 105 . 10 . 1334–42 . October 2014 . 25060424 . 4462349 . 10.1111/cas.12488 .
  32. Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, Uesugi M, Agoulnik S, Taylor N, Funahashi Y, Matsui J . Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states . British Journal of Cancer . 110 . 6 . 1497–505 . March 2014 . 24569463 . 3960630 . 10.1038/bjc.2014.80 .
  33. Kawano S, Asano M, Adachi Y, Matsui J . Antimitotic and Non-mitotic Effects of Eribulin Mesilate in Soft Tissue Sarcoma . Anticancer Research . 36 . 4 . 1553–61 . April 2016 . 27069131 .
  34. Laughney AM, Kim E, Sprachman MM, Miller MA, Kohler RH, Yang KS, Orth JD, Mitchison TJ, Weissleder R . Single-cell pharmacokinetic imaging reveals a therapeutic strategy to overcome drug resistance to the microtubule inhibitor eribulin . Science Translational Medicine . 6 . 261 . 261ra152 . November 2014 . 25378644 . 4330962 . 10.1126/scitranslmed.3009318 .
  35. Seletsky BM, Wang Y, Hawkins LD, Palme MH, Habgood GJ, DiPietro LV, Towle MJ, Salvato KA, Wels BF, Aalfs KK, Kishi Y, Littlefield BA, Yu MJ . Structurally simplified macrolactone analogues of halichondrin B . Bioorganic & Medicinal Chemistry Letters . 14 . 22 . 5547–50 . November 2004 . 15482921 . 10.1016/j.bmcl.2004.08.068 .
  36. Kim DS, Dong CG, Kim JT, Guo H, Huang J, Tiseni PS, Kishi Y . 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 . November 2009 . 19807076 . 10.1021/ja9058475 .
  37. Web site: 184 Studies found for: eribulin OR E7389 . ClinicalTrials.gov . U.S. National Library of Medicine.
  38. Yu Y, Desjardins C, Saxton P, Lai G, Schuck E, Wong YN . Characterization of the pharmacokinetics of a liposomal formulation of eribulin mesylate (E7389) in mice . International Journal of Pharmaceutics . 443 . 1–2 . 9–16 . February 2013 . 23313921 . 10.1016/j.ijpharm.2013.01.010 .

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