Eribulin

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Eribulin
Eribulin.svg
Clinical data
Trade names Halaven
Other namesE7389, ER-086526, NSC-707389, eribulin mesilate (JAN JP), eribulin mesylate (USAN US)
AHFS/Drugs.com Monograph
MedlinePlus a611007
License data
Pregnancy
category
Routes of
administration 		Intravenous
Drug class Antineoplastic agent
ATC code
Legal status
Legal status
Identifiers
  • 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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.230.372 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C40H59NO11
Molar mass 729.908 g·mol−1
3D model (JSmol)
  • 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
  • InChI=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 Yes check.svgY
  • Key:UFNVPOGXISZXJD-JBQZKEIOSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Eribulin, sold under the brand name Halaven among others, is an anti-cancer medication used to treat breast cancer and liposarcoma. [4] [6]

Contents

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). [9] Eribulin may also cause low levels of infection-fighting white blood cells (neutropenia) or decreased levels of potassium or calcium. [9]

Eribulin was approved for medical use in the United States in November 2010, [10] the European Union in March 2011, [6] and Canada in December 2011. [2] [11] [12]

Medical uses

Eribulin is indicated for the treatment of people with locally advanced or metastatic breast cancer, [6] [13] [14] [15] [16] [17] and for the treatment of adults with unresectable liposarcoma. [6] [9]

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. [9] [18] [ unreliable medical source? ]

Structure and mechanism

Eribulin is a fully synthetic macrocyclic ketone analog of the marine natural product halichondrin B, [19] [20] 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. [21] [22]

Eribulin is a mechanistically unique inhibitor of microtubule dynamics, [23] [24] binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules. [25] [26] 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. [27] [28] 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. [29] [30] In other studies, eribulin treatment of leiomyosarcoma and liposarcoma cells leads to increased expression of smooth muscle and adipocyte differentiation antigens, respectively. [31] 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). [32] Fluorescently labeled eribulin has been used to study the pharmacokinetics and pharmacodynamics at single cell level in vivo. [32]

The synthesis of eribulin was first published [33] in 2001; a new synthetic route to the drug was published in 2009. [34]

Society and culture

Intellectual Property

There are five active patents in the United States that are associated with the Halaven drug application, N201532. The first one expired in June 2019, the last one (USRE46965) expires in January 2027. [35]

Research

Eribulin is being investigated for use in a variety of other 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. [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. [37] 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. [39]

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References

  1. ↑ "Eribulin (Halaven) Use During Pregnancy". Drugs.com. 22 October 2019. Retrieved 9 July 2020.
  2. 1 2 "Halaven Product information". Health Canada . 22 October 2009. Retrieved 16 December 2023.
  3. ↑ "Halaven 0.44 mg/ml solution for injection". (emc). 16 January 2023. Retrieved 16 December 2023.
  4. 1 2 "Halaven- eribulin mesylate injection". DailyMed. 22 December 2017. Retrieved 9 July 2020.
  5. ↑ "U.S. FDA Approves Eisai's Anticancer Agent Halaven For The Treatment Of Advanced Liposarcoma" (Press release). Eisai Co., Ltd. 29 January 2016. Retrieved 15 February 2021.
  6. 1 2 3 4 5 "Halaven EPAR". European Medicines Agency. 17 March 2011. Retrieved 16 December 2023.
  7. ↑ "Eisai Announces Japan Launch Of Anticancer Agent Halaven" (Press release). Eisai Co., Ltd. 19 July 2011. Retrieved 15 February 2021.
  8. ↑ "Anticancer Agent Halaven Approved For Treatment Of Locally Advanced Or Metastatic Breast Cancer In China" (Press release). Eisai Co., Ltd. 17 July 2019. Retrieved 15 February 2021.
  9. 1 2 3 4 "FDA approves first drug to show survival benefit in liposarcoma". U.S. Food and Drug Administration (FDA) (Press release). 28 January 2016. Retrieved 9 July 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  10. ↑ "Drug Approval Package: Halaven (erbulin mesylate) NDA 201532". U.S. Food and Drug Administration (FDA). Retrieved 9 July 2020.
  11. ↑ "Halaven for Metastatic Breast Cancer". Canadian Agency for Drugs and Technologies in Health. 9 March 2015. Retrieved 9 July 2020.
  12. ↑ "Eisai Announces Canadian Approval of its Anticancer Agent Halaven". Eisai Co., Ltd. (Press release). Retrieved 9 July 2020.
  13. ↑ "FDA approves new treatment option for late-stage breast cancer" (Press release). U.S. Food and Drug Administration (FDA). 15 November 2010. Archived from the original on 17 November 2010. Retrieved 15 November 2010.
  14. ↑ "Eribulin". U.S. Food and Drug Administration. 28 January 2016. Retrieved 16 December 2023.
  15. ↑ Notice of Decision for Halaven [ permanent dead link ]
  16. ↑ "Halaven for Metastatic Breast Cancer". Canadian Agency for Drugs and Technologies in Health. 9 March 2015. Retrieved 9 July 2020.
  17. ↑ "Eisai Announces Canadian Approval of its Anticancer Agent Halaven". Eisai Co., Ltd. (Press release). Retrieved 9 July 2020.
  18. ↑ "Eribulin (Halaven)". Breast Cancer Now. 5 June 2015. Retrieved 15 September 2022.
  19. ↑ 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. PMID   11221827.
  20. ↑ 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. ISBN   978-0-8493-1863-4.[ page needed ]
  21. ↑ Hirata Y, Uemura D (1 January 1986). "Halichondrins - antitumor polyether macrolides from a marine sponge". Pure and Applied Chemistry. 58 (5): 701–710. doi: 10.1351/pac198658050701 . ISSN   1365-3075. S2CID   38138047.
  22. ↑ Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E (August 1991). "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. doi: 10.1016/S0021-9258(18)98491-7 . PMID   1874739.
  23. ↑ Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, et al. (July 2005). "The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth". Molecular Cancer Therapeutics. 4 (7): 1086–95. doi:10.1158/1535-7163.MCT-04-0345. PMID   16020666. S2CID   38459382.
  24. ↑ Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA (July 2008). "Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase". Molecular Cancer Therapeutics. 7 (7): 2003–11. doi:10.1158/1535-7163.MCT-08-0095. PMC   2562299 . PMID   18645010.
  25. ↑ Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, et al. (February 2010). "Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability". Biochemistry. 49 (6): 1331–7. doi:10.1021/bi901810u. PMC   2846717 . PMID   20030375.
  26. ↑ 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. PMID   26435331.
  27. ↑ Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, et al. (August 2004). "Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389". Cancer Research. 64 (16): 5760–6. doi:10.1158/0008-5472.CAN-04-1169. PMID   15313917. S2CID   30919443.
  28. ↑ Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, et al. (January 2011). "Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions". Cancer Research. 71 (2): 496–505. doi: 10.1158/0008-5472.CAN-10-1874 . PMID   21127197.
  29. ↑ Funahashi Y, Okamoto K, Adachi Y, Semba T, Uesugi M, Ozawa Y, et al. (October 2014). "Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models". Cancer Science. 105 (10): 1334–42. doi:10.1111/cas.12488. PMC   4462349 . PMID   25060424.
  30. ↑ Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, et al. (March 2014). "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. doi:10.1038/bjc.2014.80. PMC   3960630 . PMID   24569463.
  31. ↑ Kawano S, Asano M, Adachi Y, Matsui J (April 2016). "Antimitotic and Non-mitotic Effects of Eribulin Mesilate in Soft Tissue Sarcoma". Anticancer Research. 36 (4): 1553–61. PMID   27069131.
  32. 1 2 Laughney AM, Kim E, Sprachman MM, Miller MA, Kohler RH, Yang KS, et al. (November 2014). "Single-cell pharmacokinetic imaging reveals a therapeutic strategy to overcome drug resistance to the microtubule inhibitor eribulin". Science Translational Medicine. 6 (261): 261ra152. doi:10.1126/scitranslmed.3009318. PMC   4330962 . PMID   25378644.
  33. ↑ 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. PMID   15482921.
  34. ↑ 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. PMID   19807076.
  35. ↑ "Patent and Exclusivity for: N201532". Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. U.S. Food and Drug Administration.
  36. ↑ "184 Studies found for: eribulin OR E7389". ClinicalTrials.gov. U.S. National Library of Medicine.
  37. ↑ Clinical trial number NCT03207672 for "Study of E7389 Liposomal Formulation in Subjects With Solid Tumor" at ClinicalTrials.gov
  38. ↑ 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. PMID   23313921.
  39. ↑ 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
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