Chemistry:Eribulin

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Short description: Pharmaceutical drug
Eribulin
Eribulin.svg
Clinical data
Trade namesHalaven
Other namesE7389, ER-086526, NSC-707389, eribulin mesilate (JAN JP), eribulin mesylate (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa611007
License data
Pregnancy
category
Routes of
administration		Intravenous
Drug classAntineoplastic agent
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC40H59NO11
Molar mass729.908 g·mol−1
3D model (JSmol)
 ☒N☑Y (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]

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]

References

  1. ↑ "Eribulin (Halaven) Use During Pregnancy". 22 October 2019. https://www.drugs.com/pregnancy/eribulin.html. 
  2. ↑ 2.0 2.1 "Halaven Product information". 22 October 2009. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=86314. 
  3. ↑ "Halaven 0.44 mg/ml solution for injection". 16 January 2023. https://www.medicines.org.uk/emc/product/4517/smpc. 
  4. ↑ 4.0 4.1 "Halaven- eribulin mesylate injection". 22 December 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=31ce4750-ded5-4a0b-95e9-f229fa6bc822. 
  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. ↑ 6.0 6.1 6.2 6.3 6.4 "Halaven EPAR". 17 March 2011. https://www.ema.europa.eu/en/medicines/human/EPAR/halaven. 
  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. ↑ 9.0 9.1 9.2 9.3 "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. This article incorporates text from this source, which is in the public domain.
  10. ↑ "Drug Approval Package: Halaven (erbulin mesylate) NDA 201532". https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/201532s000_halaven_TOC.cfm. 
  11. ↑ "Halaven for Metastatic Breast Cancer". 9 March 2015. https://www.cadth.ca/halaven-metastatic-breast-cancer-details. 
  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). 2010-11-15. Archived from the original on November 17, 2010. Retrieved November 15, 2010.
  14. ↑ "Eribulin". 28 January 2016. https://www.fda.gov/drugs/resources-information-approved-drugs/eribulin. 
  15. ↑ Notice of Decision for Halaven[yes|permanent dead link|dead link}}]
  16. ↑ "Halaven for Metastatic Breast Cancer". 9 March 2015. https://www.cadth.ca/halaven-metastatic-breast-cancer-details. 
  17. ↑ "Eisai Announces Canadian Approval of its Anticancer Agent Halaven". Eisai Co., Ltd. (Press release). Retrieved 9 July 2020.
  18. ↑ "Eribulin (Halaven)". 2015-06-05. https://breastcancernow.org/information-support/facing-breast-cancer/going-through-treatment-breast-cancer/chemotherapy/eribulin-halaven. 
  19. ↑ "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B". Cancer Research 61 (3): 1013–21. February 2001. PMID 11221827. 
  20. ↑ "Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B". Anticancer agents from natural products. Washington, DC: Taylor & Francis. 2005. ISBN 978-0-8493-1863-4. [page needed]
  21. ↑ "Halichondrins - antitumor polyether macrolides from a marine sponge". Pure and Applied Chemistry 58 (5): 701–710. 1986-01-01. doi:10.1351/pac198658050701. ISSN 1365-3075. 
  22. ↑ "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. doi:10.1016/S0021-9258(18)98491-7. PMID 1874739. 
  23. ↑ "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. doi:10.1158/1535-7163.MCT-04-0345. PMID 16020666. 
  24. ↑ "Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase". Molecular Cancer Therapeutics 7 (7): 2003–11. July 2008. doi:10.1158/1535-7163.MCT-08-0095. PMID 18645010. 
  25. ↑ "Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability". Biochemistry 49 (6): 1331–7. February 2010. doi:10.1021/bi901810u. PMID 20030375. 
  26. ↑ "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. doi:10.1021/acs.biochem.5b00745. PMID 26435331. 
  27. ↑ "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. doi:10.1158/0008-5472.CAN-04-1169. PMID 15313917. 
  28. ↑ "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. doi:10.1158/0008-5472.CAN-10-1874. PMID 21127197. 
  29. ↑ "Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models". Cancer Science 105 (10): 1334–42. October 2014. doi:10.1111/cas.12488. PMID 25060424. 
  30. ↑ "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. doi:10.1038/bjc.2014.80. PMID 24569463. 
  31. ↑ "Antimitotic and Non-mitotic Effects of Eribulin Mesilate in Soft Tissue Sarcoma". Anticancer Research 36 (4): 1553–61. April 2016. PMID 27069131. 
  32. ↑ 32.0 32.1 "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. doi:10.1126/scitranslmed.3009318. PMID 25378644. 
  33. ↑ "Structurally simplified macrolactone analogues of halichondrin B". Bioorganic & Medicinal Chemistry Letters 14 (22): 5547–50. November 2004. doi:10.1016/j.bmcl.2004.08.068. PMID 15482921. 
  34. ↑ "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. 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. https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=001&Appl_No=201532&Appl_type=N. 
  36. ↑ "184 Studies found for: eribulin OR E7389". ClinicalTrials.gov. U.S. National Library of Medicine. http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389. 
  37. ↑ Clinical trial number NCT03207672 for "Study of E7389 Liposomal Formulation in Subjects With Solid Tumor" at ClinicalTrials.gov
  38. ↑ "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. 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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