Fulvestrant, sold under the brand nameFaslodex among others, is anantiestrogenicmedication used to treat hormone receptor (HR)-positive metastaticbreast cancer inpostmenopausal women with disease progression as well as HR-positive, HER2-negative advanced breast cancer in combination withabemaciclib orpalbociclib in women with disease progression after endocrine therapy.[2] It is given byinjection into a muscle.[5]
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.[5] A 2017 Cochrane review found it is as safe and effective as first line or second line endocrine therapy.[5]
It is also used to treat ER-positive, HER2-negative advanced or metastatic breast cancer in combination withabemaciclib orpalbociclib in women with disease progression after first-line endocrine therapy.[2]
Due to the medication's having a chemical structure similar to that ofestrogen, it can interact withimmunoassays for bloodestradiol concentrations and show falsely elevated results.[8][9][10] This can improperly lead to discontinuing the treatment.[8]
Very common (occurring in more than 10% of people) adverse effects include nausea, injection site reactions, weakness, andelevated 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, elevatedbilirubin, rashes, and back pain.[1] In a large clinical trial, the incidence ofvenous thromboembolism (VTE) with fulvestrant was 0.9%.[2]
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] Theelimination half-life of fulvestrant with intramuscular injection is 40 to 50 days.[20][2] This is 40 times longer than the half-life of fulvestrant byintravenous injection, indicating that its long half-life with intramuscular injection is due to slow absorption from the injection site.[19] Levels of fulvestrant with 500 mg/month by intramuscular injection (and a single additional 500 mgloading dose on day 15 of therapy) in postmenopausal women with advanced breast cancer were 25.1 ng/mL (25,100 pg/mL) atpeak and 28.0 ng/mL (28,000 pg/mL) attrough 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 atsteady state.[2]
Fulvestrant appears to bemetabolized along similar pathways asendogenous 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.[1]
Due to problems with the original fulvestrant synthesis starting from nandrolone,[28] an alternative method of synthesis was disclosed:[29] Starting materials:[30][31]
Treatment of 6-Ketoestradiol [571-92-6] (1) with acetic anhydride gives 6-Oxoestradiol diacetate [3434-45-5] (2). Reaction of 9-[(4,4,5,5,5-Pentafluoropentyl)sulfanyl]nonan-1-ol [511545-94-1] (3) with mesyl chloride followed by displacement with potassium iodide gives 1-Iodo-9-[(4,4,5,5,5-pentafluoropentyl)thio]nonane [862700-63-8] (4). Reaction of2 with potassium tert-butoxide followed by addition of4 gives PC71724892 (5). Catalytic hydrogenation reduces the benzoyl ketone to give (6).Saponification of the acetyl protecting groups gives [153004-31-0] (7). Lastly, oxidation of the sulfanyl group withsodium periodate gives the sulfoxide, completing the synthesis of fulvestrant (8).
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'sNational 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] In the 12 months ending June 2015, the UK price (excluding VAT) of a month's supply ofanastrozole (Arimidex), which is off patent, cost 89 pence/day, andletrozole (Femara) cost £1.40/day.[34][35][36]
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.[37][38]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.[39] A later patent for Faslodex expires in January 2021.[40] Atossa Genetics has a patent for the administration of fulvestrant into the breast via a microcatheter invented bySusan Love.[41]
Fulvestrant was studied inendometrial cancer but results were not promising and as of 2016 development for this use was abandoned.[42]
Because fulvestrant cannot be given orally, efforts have been made to developSERD drugs that can be taken by mouth, includingbrilanestrant andelacestrant.[6] The clinical success of fulvestrant also led to efforts to discover and develop a parallel drug class ofselective androgen receptor degraders (SARDs).[6]
^Samuel E, Chiang C, Jennens R, Faulkner D, Francis PA (February 2020). "Fulvestrant falsely elevates oestradiol levels in immunoassays in postmenopausal women with breast cancer".Eur J Cancer.126:104–105.doi:10.1016/j.ejca.2019.10.015.PMID31927211.S2CID210166996.
^abcCroxtall JD, McKeage K (February 2011). "Fulvestrant: a review of its use in the management of hormone receptor-positive metastatic breast cancer in postmenopausal women".Drugs.71 (3):363–80.doi:10.2165/11204810-000000000-00000.PMID21319872.S2CID249870430.
^Moffat JG, Rudolph J, Bailey D (August 2014). "Phenotypic screening in cancer drug discovery - past, present and future".Nature Reviews. Drug Discovery.13 (8):588–602.doi:10.1038/nrd4366.PMID25033736.S2CID5964541.
^Lednicer, D. (2015).Antineoplastic drugs: organic syntheses. Wiley.ISBN9781118892541.
^陈玮琳, et al. CN102993257 (2013 to HUZHOU RONGDA MEDICINE CO Ltd).
^周海亮, et al. CN116003502 (2023 to Jiangxi Junye Biological Pharmaceutical Co ltd).
^曹莹, et al. CN111377997 (2020 to Jiangsu Hansoh Pharmaceutical Group Co Ltd).
^提文利 & 程磊, CN114685593 (2024 to Lunan Pharmaceutical Group Corp).
^Durga Prasad Konakanchi, et al. WO2017064724 (to Natco Pharma Ltd).
^US granted 6638727, Hung DT, Love S, "Methods for identifying treating or monitoring asymptomatic patients for risk reduction or therapeutic treatment of breast cancer", issued 28 October 2003, assigned to Cytyc Health Corp
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