fulvestrant

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. A 2017 Cochrane review found it is as safe and effective as first line or second line endocrine therapy.

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.{{cite web|title=Estradiol immunoassays – interference from the drug fulvestrant (Faslodex®) may cause falsely elevated estradiol results Medical safety alert - GOV.UK|url=https://www.gov.uk/drug-device-alerts/-estradiol-immunoassays-interference-from-the-drug-fulvestrant-faslodex-may-cause-falsely-elevated-estradiol-results|publisher=UK Medicines and Healthcare products Regulatory Agency|language=en|date=24 March 2016|access-date=2 May 2016|archive-date=19 July 2017|archive-url=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|url-status=dead}}{{cite journal | vauthors = Owen LJ, Monaghan PJ, Armstrong A, Keevil BG, Higham C, Salih Z, Howell S | title = Oestradiol measurement during fulvestrant treatment for breast cancer | journal = Br J Cancer | volume = 120 | issue = 4 | pages = 404–406 | date = February 2019 | pmid = 30679781 | pmc = 6461991 | doi = 10.1038/s41416-019-0378-9 | url = }}{{cite journal | vauthors = Samuel E, Chiang C, Jennens R, Faulkner D, Francis PA | title = Fulvestrant falsely elevates oestradiol levels in immunoassays in postmenopausal women with breast cancer | journal = Eur J Cancer | volume = 126 | issue = | pages = 104–105 | date = February 2020 | pmid = 31927211 | doi = 10.1016/j.ejca.2019.10.015 | s2cid = 210166996 | url = }} This can improperly lead to discontinuing the treatment.

Fulvestrant has been used in the treatment of peripheral precocious puberty in girls with McCune–Albright syndrome.{{cite journal | vauthors = Fuqua JS | title = Treatment and outcomes of precocious puberty: an update | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 98 | issue = 6 | pages = 2198–207 | date = June 2013 | pmid = 23515450 | doi = 10.1210/jc.2013-1024 | doi-access = free }}{{cite book | vauthors = Zacharin M | title = Pediatric Pharmacotherapy | chapter = Disorders of Puberty: Pharmacotherapeutic Strategies for Management | series = Handbook of Experimental Pharmacology | date = May 2019 | volume = 261 | pages = 507–538 | publisher = Springer | pmid = 31144045 | doi = 10.1007/164_2019_208 | isbn = 978-3-030-50493-9 | s2cid = 169040406 }}{{cite journal | vauthors = Sims EK, Garnett S, Guzman F, Paris F, Sultan C, Eugster EA | title = Fulvestrant treatment of precocious puberty in girls with McCune-Albright syndrome | journal = International Journal of Pediatric Endocrinology | volume = 2012 | issue = 1 | pages = 26 | date = September 2012 | pmid = 22999294 | pmc = 3488024 | doi = 10.1186/1687-9856-2012-26 | doi-access = free }}

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.

Fulvestrant should not be used in women with kidney failure or who are pregnant.{{cite web|title=Faslodex 250 mg solution for injection - Summary of Product Characteristics|url=https://www.medicines.org.uk/emc/medicine/14381|publisher=UK Electronic Medicines Compendium|date=21 July 2016|access-date=25 January 2017|archive-date=10 October 2021|archive-url=https://web.archive.org/web/20211010195002/https://www.medicines.org.uk/emc/medicine/14381|url-status=live}}

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. In a large clinical trial, the incidence of venous thromboembolism (VTE) with fulvestrant was 0.9%.

Fulvestrant is an antiestrogen which acts as an antagonist of the estrogen receptor (ER) and additionally as a selective estrogen receptor degrader (SERD). 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.

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).{{cite journal | vauthors = Prossnitz ER, Arterburn JB | title = International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators | journal = Pharmacol. Rev. | volume = 67 | issue = 3 | pages = 505–40 | date = July 2015 | pmid = 26023144 | pmc = 4485017 | doi = 10.1124/pr.114.009712 }}{{cite journal | vauthors = Thomas P, Pang Y, Filardo EJ, Dong J | title = Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells | journal = Endocrinology | volume = 146 | issue = 2 | pages = 624–32 | date = February 2005 | pmid = 15539556 | doi = 10.1210/en.2004-1064 | doi-access = free }}{{cite journal | vauthors = Prossnitz ER, Barton M | title = The G-protein-coupled estrogen receptor GPER in health and disease | journal = Nat Rev Endocrinol | volume = 7 | issue = 12 | pages = 715–26 | date = August 2011 | pmid = 21844907 | pmc = 3474542 | doi = 10.1038/nrendo.2011.122 }}{{cite journal | vauthors = Prossnitz ER, Barton M | title = Estrogen biology: new insights into GPER function and clinical opportunities | journal = Mol. Cell. Endocrinol. | volume = 389 | issue = 1–2 | pages = 71–83 | date = May 2014 | pmid = 24530924 | pmc = 4040308 | doi = 10.1016/j.mce.2014.02.002 }}{{cite journal | vauthors = Barton M | title = Position paper: The membrane estrogen receptor GPER--Clues and questions | journal = Steroids | volume = 77 | issue = 10 | pages = 935–42 | date = August 2012 | pmid = 22521564 | doi = 10.1016/j.steroids.2012.04.001 | s2cid = 35909008 | doi-access = free }}

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.{{cite journal | vauthors = Robertson JF, Harrison M | title = Fulvestrant: pharmacokinetics and pharmacology | journal = Br J Cancer | volume = 90 | pages = S7–10 | date = March 2004 | issue = Suppl 1 | pmid = 15094758 | pmc = 2750771 | doi = 10.1038/sj.bjc.6601630 }} 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.{{cite journal | vauthors = Robertson JF | title = ICI 182,780 (Fulvestrant)--the first oestrogen receptor down-regulator--current clinical data | journal = Br. J. Cancer | volume = 85 | pages = 11–4 | date = November 2001 | issue = Suppl 2 | pmid = 11900210 | pmc = 2375169 | doi = 10.1054/bjoc.2001.1982 | doi-broken-date = 1 November 2024 }}{{cite journal | vauthors = Howell A, Abram P | title = Clinical development of fulvestrant ("Faslodex") | journal = Cancer Treat. Rev. | volume = 31 | pages = S3–9 | date = 2005 | issue = Suppl 2 | pmid = 16198055 | doi = 10.1016/j.ctrv.2005.08.010 }}{{cite journal | vauthors = Bundred N, Howell A | title = Fulvestrant (Faslodex): current status in the therapy of breast cancer | journal = Expert Rev Anticancer Ther | volume = 2 | issue = 2 | pages = 151–60 | date = April 2002 | pmid = 12113237 | doi = 10.1586/14737140.2.2.151 | s2cid = 20294814 }} Accordingly, no effects of fulvestrant on brain function have been observed in preclinical or clinical research. Fulvestrant is highly (99%) bound to plasma proteins.{{cite journal | vauthors = Croxtall JD, McKeage K | title = Fulvestrant: a review of its use in the management of hormone receptor-positive metastatic breast cancer in postmenopausal women | journal = Drugs | volume = 71 | issue = 3 | pages = 363–80 | date = February 2011 | pmid = 21319872 | doi = 10.2165/11204810-000000000-00000 | s2cid = 249870430 }} 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.

Fulvestrant can form colloidal aggregates at certain concentration ranges and this can limit its activity as well as produce bell-shaped concentration–response curves.{{cite journal | vauthors = Ganesh AN, Donders EN, Shoichet BK, Shoichet MS | title = Colloidal aggregation: from screening nuisance to formulation nuance | journal = Nano Today | volume = 19 | pages = 188–200 | date = April 2018 | pmid = 30250495 | pmc = 6150470 | doi = 10.1016/j.nantod.2018.02.011 }}{{cite journal | vauthors = Ganesh AN, Aman A, Logie J, Barthel BL, Cogan P, Al-Awar R, Koch TH, Shoichet BK, Shoichet MS | title = Colloidal Drug Aggregate Stability in High Serum Conditions and Pharmacokinetic Consequence | journal = ACS Chem Biol | volume = 14 | issue = 4 | pages = 751–757 | date = April 2019 | pmid = 30840432 | pmc = 6474797 | doi = 10.1021/acschembio.9b00032 }}{{cite journal | vauthors = Owen SC, Doak AK, Ganesh AN, Nedyalkova L, McLaughlin CK, Shoichet BK, Shoichet MS | title = Colloidal drug formulations can explain "bell-shaped" concentration-response curves | journal = ACS Chem Biol | volume = 9 | issue = 3 | pages = 777–84 | date = March 2014 | pmid = 24397822 | pmc = 3985758 | doi = 10.1021/cb4007584 }}

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.

It was discovered through rational drug design, but was selected for further development via phenotypic screening.{{cite journal | vauthors = Moffat JG, Rudolph J, Bailey D | title = Phenotypic screening in cancer drug discovery - past, present and future | journal = Nature Reviews. Drug Discovery | volume = 13 | issue = 8 | pages = 588–602 | date = August 2014 | pmid = 25033736 | doi = 10.1038/nrd4366 | s2cid = 5964541 }}

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

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.{{citation needed|date=May 2016}} 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.[https://www.gov.uk/government/publications/drugs-and-pharmaceutical-electronic-market-information-emit UK Department of Health Commercial Medicines Unit Electronic Medicines Information Tool] {{Webarchive|url=https://web.archive.org/web/20210817203140/https://www.gov.uk/government/publications/drugs-and-pharmaceutical-electronic-market-information-emit |date=17 August 2021 }}, London, 2015[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] {{Webarchive|url=https://web.archive.org/web/20120426184813/http://www.thepharmaletter.com/file/108724/uks-nice-says-no-to-astrazeneca-breast-cancer-drug-faslodex.html |date=26 April 2012 }}, The Pharma Letter, 10 November 2011[http://guidance.nice.org.uk/TA/Wave23/15 National Institute for Health and Clinical Excellence Guidance] {{Webarchive|url=https://web.archive.org/web/20110403012825/http://guidance.nice.org.uk/TA/Wave23/15 |date=3 April 2011 }} Breast cancer (metastatic) - fulvestrant

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.[http://www.uspto.gov/patents/resources/terms/156.jsp Patent Term Extensions] {{Webarchive|url=https://web.archive.org/web/20150108091004/http://www.uspto.gov/patents/resources/terms/156.jsp |date=8 January 2015 }} The United States Patent and Trademark Office.[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] {{Webarchive|url=https://web.archive.org/web/20211101234940/https://www.federalregister.gov/documents/2003/04/17/03-9536/determination-of-regulatory-review-period-for-purposes-of-patent-extension-faslodex |date=1 November 2021 }} A Notice by the Food and Drug Administration on 17 April 2003

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.[https://www.drugs.com/availability/generic-faslodex.html Generic Faslodex Availability] {{Webarchive|url=https://web.archive.org/web/20170731071226/https://www.drugs.com/availability/generic-faslodex.html |date=31 July 2017 }}, Drugs.COM A later patent for Faslodex expires in January 2021.[https://books.google.com/books?id=zVQMp4KJyeEC&dq=faslodex+patent+expiration&pg=PA199 Pink Ribbon Blues: How Breast Cancer Culture Undermines Women's Health] {{Webarchive|url=https://web.archive.org/web/20230919015930/https://books.google.com/books?id=zVQMp4KJyeEC&dq=faslodex+patent+expiration&pg=PA199 |date=19 September 2023 }} By Gayle A. Sulik, Oxford University Press (Oct. 2010) Atossa Genetics has a patent for the administration of fulvestrant into the breast via a microcatheter invented by Susan Love.{{cite patent | country = US | number = 6638727 | status = granted | gdate = 28 October 2003 | title = Methods for identifying treating or monitoring asymptomatic patients for risk reduction or therapeutic treatment of breast cancer | inventor = Hung DT, Love S | assign1 = Cytyc Health Corp }}

Fulvestrant was studied in endometrial cancer but results were not promising and as of 2016 development for this use was abandoned.{{cite journal | vauthors = Battista MJ, Schmidt M | title = Fulvestrant for the treatment of endometrial cancer | journal = Expert Opinion on Investigational Drugs | volume = 25 | issue = 4 | pages = 475–83 | date = 2016 | pmid = 26882357 | doi = 10.1517/13543784.2016.1154532 | s2cid = 207477738 }}

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

ZB716, or fulvestrant-3-boronic acid, is an oral prodrug of fulvestrant which is under development.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{{cite journal | vauthors = 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 | title = Fulvestrant-3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD) | journal = J. Med. Chem. | volume = 59 | issue = 17 | pages = 8134–40 | year = 2016 | pmid = 27529700 | doi = 10.1021/acs.jmedchem.6b00753 | pmc = 5499704 }}{{Cite web |url=https://www.clinicaltrials.gov/ct2/show/NCT04669587?term=NCT04669587&draw=2&rank=1 |title=ClinicalTrials.gov: NCT04669587 |access-date=4 January 2021 |archive-date=1 November 2021 |archive-url=https://web.archive.org/web/20211101235031/https://www.clinicaltrials.gov/ct2/show/NCT04669587?term=NCT04669587&draw=2&rank=1 |url-status=live }}

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