Fulvestrant Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:410130476
Width:250
Pronounce:
Tradename:Faslodex, others
Dailymedid:Fulvestrant
Pregnancy Au:D
Routes Of Administration:Intramuscular injection
Class:Antiestrogen
Atc Prefix:L02
Atc Suffix:BA03
Legal Au:S4
Legal Uk:POM
Legal Us:Rx-only
Legal Us Comment:[1]
Legal Eu:Rx-only
Legal Eu Comment:[2]
Legal Status:Rx-only
Bioavailability:Low
Protein Bound:99%
Metabolism:Hydroxylation, conjugation (glucuronidation, sulfation)
Elimination Half-Life:

40–50 days[3]

Cas Number:129453-61-8
Pubchem:104741
Iuphar Ligand:1015
Drugbank:DB00947
Chemspiderid:94553
Unii:22X328QOC4
Kegg:D01161
Chebi:31638
Chembl:1358
Synonyms:ICI-182780; ZD-182780; ZD-9238; 7α-[9-[(4,4,5,5,5-Pentafluoropentyl)-sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17β-diol
Iupac Name:(7R,8R,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[''a'']phenanthrene-3,17-diol
C:32
H:47
F:5
O:3
S:1
Smiles:C[C@]12CC[C@@H]3c4ccc(O)cc4CC(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O
Stdinchi:1S/C32H47F5O3S/c1-30-17-15-26-25-12-11-24(38)21-23(25)20-22(29(26)27(30)13-14-28(30)39)10-7-5-3-2-4-6-8-18-41(40)19-9-16-31(33,34)32(35,36)37/h11-12,21-22,26-29,38-39H,2-10,13-20H2,1H3/t22-,26-,27+,28+,29-,30+,41?/m1/s1
Stdinchikey:VWUXBMIQPBEWFH-WCCTWKNTSA-N

Fulvestrant, sold under the brand name Faslodex among others, is an antiestrogenic medication used to treat hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women with disease progression as well as HR-positive, HER2-negative advanced breast cancer in combination with abemaciclib or palbociclib in women with disease progression after endocrine therapy. It is given by injection into a muscle.[4]

Fulvestrant is a selective estrogen receptor degrader (SERD) and was first-in-class to be approved.[5] It works by binding to the estrogen receptor and destabilizing it, causing the cell's normal protein degradation processes to destroy it.[5]

Fulvestrant was approved for medical use in the United States in 2002.[6]

Medical uses

Breast cancer

Fulvestrant is used for the treatment of hormone receptor positive metastatic breast cancer or locally advanced unresectable disease in postmenopausal women; it is given by injection.[4] A 2017 Cochrane review found it is as safe and effective as first line or second line endocrine therapy.[4]

It is also used to treat ER-positive, HER2-negative advanced or metastatic breast cancer in combination with abemaciclib or palbociclib in women with disease progression after first-line endocrine therapy.

Due to the medication's having a chemical structure similar to that of estrogen, it can interact with immunoassays for blood estradiol concentrations and show falsely elevated results.[7] [8] [9] This can improperly lead to discontinuing the treatment.[7]

Early puberty

Fulvestrant has been used in the treatment of peripheral precocious puberty in girls with McCune–Albright syndrome.[10] [11] [12]

Available forms

Fulvestrant is provided in a castor oil solution also containing alcohol, benzyl alcohol, and benzyl benzoate. It is supplied at a concentration of 250 mg/5 mL.

Contraindications

Fulvestrant should not be used in women with kidney failure or who are pregnant.[13]

Side effects

Very common (occurring in more than 10% of people) adverse effects include nausea, injection site reactions, weakness, and elevated transaminases. Common (between 1% and 10%) adverse effects include urinary tract infections, hypersensitivity reactions, loss of appetite, headache, blood clots in veins, hot flushes, vomiting, diarrhea, elevated bilirubin, rashes, and back pain.[13] In a large clinical trial, the incidence of venous thromboembolism (VTE) with fulvestrant was 0.9%.

Pharmacology

Pharmacodynamics

Fulvestrant is an antiestrogen which acts as an antagonist of the estrogen receptor (ER) and additionally as a selective estrogen receptor degrader (SERD).[5] It works by binding to the estrogen receptor and making it more hydrophobic, which makes the receptor unstable and misfold, which in turn leads normal processes inside the cell to degrade it.[5]

In addition to its antiestrogenic activity, fulvestrant is an agonist of the G protein-coupled estrogen receptor (GPER), albeit with relatively low affinity (10–100 nM, relative to 3–6 nM for estradiol).[14] [15] [16] [17] [18]

Pharmacokinetics

Fulvestrant after an intramuscular injection is slowly absorbed and maximal levels (Cmax) are reached after 5 days on average with a range of 2 to 19 days.[19] The elimination half-life of fulvestrant with intramuscular injection is 40 to 50 days. This is 40 times longer than the half-life of fulvestrant by intravenous injection, indicating that its long half-life with intramuscular injection is due to slow absorption from the injection site. Levels of fulvestrant with 500 mg/month by intramuscular injection (and a single additional 500 mg loading dose on day 15 of therapy) in postmenopausal women with advanced breast cancer were 25.1 ng/mL (25,100 pg/mL) at peak and 28.0 ng/mL (28,000 pg/mL) at trough with a single dose and 28.0 ng/mL (28,000 pg/mL) at peak and 12.2 ng/mL (12,200 pg/mL) at trough after multiple doses at steady state.

Fulvestrant does not cross the blood–brain barrier in animals and may not in humans as well.[20] [21] [22] Accordingly, no effects of fulvestrant on brain function have been observed in preclinical or clinical research. Fulvestrant is highly (99%) bound to plasma proteins.[23] It is bound to very low density lipoprotein, low density lipoprotein, and high density lipoprotein, but not to sex hormone-binding globulin.

Fulvestrant appears to be metabolized along similar pathways as endogenous steroids; CYP3A4 may be involved, but non-cytochrome P450 routes appear to be more important. It does not inhibit any cytochrome P450 enzymes. Elimination is almost all via feces.[13]

Fulvestrant can form colloidal aggregates at certain concentration ranges and this can limit its activity as well as produce bell-shaped concentration–response curves.[24] [25] [26]

Chemistry

Fulvestrant, also known as 7α-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estradiol, is a synthetic estrane steroid and a derivative of estradiol. An alkyl-sulfinyl moiety was added to the endogenous estrogen receptor ligand.[5]

It was discovered through rational drug design, but was selected for further development via phenotypic screening.[27]

History

Fulvestrant was the first selective estrogen receptor degrader to be approved.[5] It was approved in the United States in 2002 and in the European Union in 2004.[13]

Society and culture

NICE evaluation

The U.K. National Institute for Health and Clinical Excellence (NICE) said in 2011 that it found no evidence Faslodex was significantly better than existing treatments, so its widespread use would not be a good use of resources for the country's National Health Service. The first month's treatment of Faslodex, which starts with a loading dose, costs £1,044.82 ($1,666), and subsequent treatments cost £522.41 a month. In the 12 months ending June 2015, the UK price (excluding VAT) of a month's supply of anastrozole (Arimidex), which is off patent, cost 89 pence/day, and letrozole (Femara) cost £1.40/day.[28] [29] [30]

Patent extension

The original patent for Faslodex expired in October 2004. Drugs subject to pre-marketing regulatory review are eligible for patent extension, and for this reason AstraZeneca got an extension of the patent to December 2011.[31] [32] AstraZeneca has filed later patents. A generic version of Faslodex has been approved by the FDA. However, this does not mean that the product will necessarily be commercially available - possibly because of drug patents and/or drug exclusivity.[33] A later patent for Faslodex expires in January 2021.[34] Atossa Genetics has a patent for the administration of fulvestrant into the breast via a microcatheter invented by Susan Love.[35]

Research

Fulvestrant was studied in endometrial cancer but results were not promising and as of 2016 development for this use was abandoned.[36]

Because fulvestrant cannot be given orally, efforts have been made to develop SERD drugs that can be taken by mouth, including brilanestrant and elacestrant.[5] The clinical success of fulvestrant also led to efforts to discover and develop a parallel drug class of selective androgen receptor degraders (SARDs).[5]

ZB716, or fulvestrant-3-boronic acid, is an oral prodrug of fulvestrant which is under development.[37] [38] [39]

Notes and References

  1. Web site: Faslodex- fulvestrant injection . DailyMed . 25 September 2020 . 24 May 2024 . 11 December 2023 . https://web.archive.org/web/20231211231649/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=83d7a440-e904-4e36-afb5-cb02b1c919f7 . live .
  2. Web site: Faslodex . European Medicines Agency (EMA) . 10 March 2004 . 24 May 2024 . 19 October 2021 . https://web.archive.org/web/20211019022354/https://www.ema.europa.eu/en/medicines/human/EPAR/faslodex . live .
  3. Book: Dörwald, Florencio Zaragoza . Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds . 4 February 2013 . John Wiley & Sons . 978-3-527-64565-7 . 486– . 20 May 2018 . 12 January 2023 . https://web.archive.org/web/20230112174738/https://books.google.com/books?id=YTeY9ZEfNccC&pg=PA486 . live .
  4. Lee CI, Goodwin A, Wilcken N . Fulvestrant for hormone-sensitive metastatic breast cancer . The Cochrane Database of Systematic Reviews . 1 . CD011093 . January 2017 . 1 . 28043088 . 6464820 . 10.1002/14651858.CD011093.pub2 .
  5. Lai AC, Crews CM . Induced protein degradation: an emerging drug discovery paradigm . Nature Reviews. Drug Discovery . 16 . 2 . 101–114 . February 2017 . 27885283 . 5684876 . 10.1038/nrd.2016.211 .
  6. Web site: Fulvestrant. The American Society of Health-System Pharmacists. 8 January 2017. 2 February 2017. https://web.archive.org/web/20170202013913/https://www.drugs.com/monograph/fulvestrant.html. live.
  7. Web site: Estradiol immunoassays – interference from the drug fulvestrant (Faslodex®) may cause falsely elevated estradiol results Medical safety alert - GOV.UK. UK Medicines and Healthcare products Regulatory Agency. en. 24 March 2016. 2 May 2016. 19 July 2017. https://web.archive.org/web/20170719083729/https://www.gov.uk/drug-device-alerts/-estradiol-immunoassays-interference-from-the-drug-fulvestrant-faslodex-may-cause-falsely-elevated-estradiol-results. dead.
  8. Owen LJ, Monaghan PJ, Armstrong A, Keevil BG, Higham C, Salih Z, Howell S . Oestradiol measurement during fulvestrant treatment for breast cancer . Br J Cancer . 120 . 4 . 404–406 . February 2019 . 30679781 . 6461991 . 10.1038/s41416-019-0378-9 .
  9. Samuel E, Chiang C, Jennens R, Faulkner D, Francis PA . Fulvestrant falsely elevates oestradiol levels in immunoassays in postmenopausal women with breast cancer . Eur J Cancer . 126 . 104–105 . February 2020 . 31927211 . 10.1016/j.ejca.2019.10.015 . 210166996 .
  10. Fuqua JS . Treatment and outcomes of precocious puberty: an update . The Journal of Clinical Endocrinology and Metabolism . 98 . 6 . 2198–207 . June 2013 . 23515450 . 10.1210/jc.2013-1024 . free .
  11. Book: Zacharin M . Pediatric Pharmacotherapy . Disorders of Puberty: Pharmacotherapeutic Strategies for Management . Handbook of Experimental Pharmacology . May 2019 . 261 . 507–538 . Springer . 31144045 . 10.1007/164_2019_208 . 978-3-030-50493-9 . 169040406 .
  12. Sims EK, Garnett S, Guzman F, Paris F, Sultan C, Eugster EA . Fulvestrant treatment of precocious puberty in girls with McCune-Albright syndrome . International Journal of Pediatric Endocrinology . 2012 . 1 . 26 . September 2012 . 22999294 . 3488024 . 10.1186/1687-9856-2012-26 . free .
  13. Web site: Faslodex 250 mg solution for injection - Summary of Product Characteristics. UK Electronic Medicines Compendium. 21 July 2016. 25 January 2017. 10 October 2021. https://web.archive.org/web/20211010195002/https://www.medicines.org.uk/emc/medicine/14381. live.
  14. Prossnitz ER, Arterburn JB . International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators . Pharmacol. Rev. . 67 . 3 . 505–40 . July 2015 . 26023144 . 4485017 . 10.1124/pr.114.009712 .
  15. Thomas P, Pang Y, Filardo EJ, Dong J . Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells . Endocrinology . 146 . 2 . 624–32 . February 2005 . 15539556 . 10.1210/en.2004-1064 . free .
  16. Prossnitz ER, Barton M . The G-protein-coupled estrogen receptor GPER in health and disease . Nat Rev Endocrinol . 7 . 12 . 715–26 . August 2011 . 21844907 . 3474542 . 10.1038/nrendo.2011.122 .
  17. Prossnitz ER, Barton M . Estrogen biology: new insights into GPER function and clinical opportunities . Mol. Cell. Endocrinol. . 389 . 1–2 . 71–83 . May 2014 . 24530924 . 4040308 . 10.1016/j.mce.2014.02.002 .
  18. Barton M . Position paper: The membrane estrogen receptor GPER--Clues and questions . Steroids . 77 . 10 . 935–42 . August 2012 . 22521564 . 10.1016/j.steroids.2012.04.001 . 35909008 . free .
  19. Robertson JF, Harrison M . Fulvestrant: pharmacokinetics and pharmacology . Br J Cancer . 90 . S7–10 . March 2004 . Suppl 1 . 15094758 . 2750771 . 10.1038/sj.bjc.6601630 .
  20. Robertson JF . ICI 182,780 (Fulvestrant)--the first oestrogen receptor down-regulator--current clinical data . Br. J. Cancer . 85 . 11–4 . November 2001 . Suppl 2 . 11900210 . 2375169 . 10.1054/bjoc.2001.1982 . 31 January 2024 .
  21. Howell A, Abram P . Clinical development of fulvestrant ("Faslodex") . Cancer Treat. Rev. . 31 . S3–9 . 2005 . Suppl 2 . 16198055 . 10.1016/j.ctrv.2005.08.010 .
  22. Bundred N, Howell A . Fulvestrant (Faslodex): current status in the therapy of breast cancer . Expert Rev Anticancer Ther . 2 . 2 . 151–60 . April 2002 . 12113237 . 10.1586/14737140.2.2.151 . 20294814 .
  23. Croxtall JD, McKeage K . Fulvestrant: a review of its use in the management of hormone receptor-positive metastatic breast cancer in postmenopausal women . Drugs . 71 . 3 . 363–80 . February 2011 . 21319872 . 10.2165/11204810-000000000-00000 . 249870430 .
  24. Ganesh AN, Donders EN, Shoichet BK, Shoichet MS . Colloidal aggregation: from screening nuisance to formulation nuance . Nano Today . 19 . 188–200 . April 2018 . 30250495 . 6150470 . 10.1016/j.nantod.2018.02.011 .
  25. Ganesh AN, Aman A, Logie J, Barthel BL, Cogan P, Al-Awar R, Koch TH, Shoichet BK, Shoichet MS . Colloidal Drug Aggregate Stability in High Serum Conditions and Pharmacokinetic Consequence . ACS Chem Biol . 14 . 4 . 751–757 . April 2019 . 30840432 . 6474797 . 10.1021/acschembio.9b00032 .
  26. Owen SC, Doak AK, Ganesh AN, Nedyalkova L, McLaughlin CK, Shoichet BK, Shoichet MS . Colloidal drug formulations can explain "bell-shaped" concentration-response curves . ACS Chem Biol . 9 . 3 . 777–84 . March 2014 . 24397822 . 3985758 . 10.1021/cb4007584 .
  27. Moffat JG, Rudolph J, Bailey D . Phenotypic screening in cancer drug discovery - past, present and future . Nature Reviews. Drug Discovery . 13 . 8 . 588–602 . August 2014 . 25033736 . 10.1038/nrd4366 . 5964541 .
  28. https://www.gov.uk/government/publications/drugs-and-pharmaceutical-electronic-market-information-emit UK Department of Health Commercial Medicines Unit Electronic Medicines Information Tool
  29. http://www.thepharmaletter.com/file/108724/uks-nice-says-no-to-astrazeneca-breast-cancer-drug-faslodex.html UK’s NICE says no to AstraZeneca breast cancer drug Faslodex
  30. http://guidance.nice.org.uk/TA/Wave23/15 National Institute for Health and Clinical Excellence Guidance
  31. http://www.uspto.gov/patents/resources/terms/156.jsp Patent Term Extensions
  32. http://www.federalregister.gov/articles/2003/04/17/03-9536/determination-of-regulatory-review-period-for-purposes-of-patent-extension-faslodex Determination of Regulatory Review Period for Purposes of Patent Extension; FASLODEX
  33. https://www.drugs.com/availability/generic-faslodex.html Generic Faslodex Availability
  34. https://books.google.com/books?id=zVQMp4KJyeEC&dq=faslodex+patent+expiration&pg=PA199 Pink Ribbon Blues: How Breast Cancer Culture Undermines Women's Health
  35. US . 6638727 . granted . 28 October 2003 . Methods for identifying treating or monitoring asymptomatic patients for risk reduction or therapeutic treatment of breast cancer . Hung DT, Love S . Cytyc Health Corp .
  36. Battista MJ, Schmidt M . Fulvestrant for the treatment of endometrial cancer . Expert Opinion on Investigational Drugs . 25 . 4 . 475–83 . 2016 . 26882357 . 10.1517/13543784.2016.1154532 . 207477738 .
  37. Ahmad, I., Mathew, S., & Rahman, S. (2020). Recent progress in selective estrogen receptor downregulators (SERDs) for the treatment of breast cancer. RSC Medicinal Chemistry, 11(4), 438–454. https://doi.org/10.1039/C9MD00570F
  38. Liu J, Zheng S, Akerstrom VL, Yuan C, Ma Y, Zhong Q, Zhang C, Zhang Q, Guo S, Ma P, Skripnikova EV, Bratton MR, Pannuti A, Miele L, Wiese TE, Wang G . Fulvestrant-3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD) . J. Med. Chem. . 59 . 17 . 8134–40 . 2016 . 27529700 . 10.1021/acs.jmedchem.6b00753 . 5499704 .
  39. Web site: ClinicalTrials.gov: NCT04669587 . 4 January 2021 . 1 November 2021 . https://web.archive.org/web/20211101235031/https://www.clinicaltrials.gov/ct2/show/NCT04669587?term=NCT04669587&draw=2&rank=1 . live .

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