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.
Fulvestrant is a selective estrogen receptor degrader (SERD) and was first-in-class to be approved. It works by binding to the estrogen receptor and destabilizing it, causing the cell's normal protein degradation processes to destroy it.
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. This can improperly lead to discontinuing the treatment.
Available forms
Fulvestrant is provided in a castor oil solution also containing alcohol, benzyl alcohol, and benzyl benzoate.
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.
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. The elimination half-life of fulvestrant with intramuscular injection is 40 to 50 days. Accordingly, no effects of fulvestrant on brain function have been observed in preclinical or clinical research.
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.
Synthesis
Due to problems with the original fulvestrant synthesis starting from nandrolone, an alternative method of synthesis was disclosed: Starting materials:
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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 of 2 with potassium tert-butoxide followed by addition of 4 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 with sodium periodate gives the sulfoxide, completing the synthesis of fulvestrant (8).
Alternative syntheses: etc.
History
Fulvestrant was the first selective estrogen receptor degrader to be approved.
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.
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. A later patent for Faslodex expires in January 2021. Atossa Genetics has a patent for the administration of fulvestrant into the breast via a microcatheter invented by Susan Love.
Research
Fulvestrant was studied in endometrial cancer but results were not promising and as of 2016 development for this use was abandoned.
Because fulvestrant cannot be given orally, efforts have been made to develop SERD drugs that can be taken by mouth, including brilanestrant and elacestrant.