Fulvestrant, sold under the brand name Faslodex among others, is an
antiestrogenic medication
Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
used to treat hormone receptor (HR)-positive metastatic
breast cancer
Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
in
postmenopausal
Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...
women with disease progression as well as HR-positive, HER2-negative advanced breast cancer in combination with
abemaciclib or
palbociclib
Palbociclib, sold under the brand name Ibrance among others, is a medication developed by Pfizer for the treatment of HR-positive and HER2-negative breast cancer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. Palb ...
in women with disease progression after endocrine therapy.
It is given by
injection into a muscle
Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...
.
Fulvestrant is a
selective estrogen receptor degrader (SERD) and was first-in-class to be approved.
It works by binding to the
estrogen receptor
Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...
and destabilizing it, causing the cell's normal
protein degradation processes to destroy it.
[
Fulvestrant was approved for medical use in the United States in 2002.]
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.[
It is also used to treat ER-positive, HER2-negative advanced or metastatic breast cancer in combination with abemaciclib or ]palbociclib
Palbociclib, sold under the brand name Ibrance among others, is a medication developed by Pfizer for the treatment of HR-positive and HER2-negative breast cancer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. Palb ...
in women with disease progression after first-line endocrine therapy.estrogen
Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
, it can interact with immunoassay
An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoassay ...
s for blood estradiol
Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...
concentrations and show falsely elevated results.[
]
Early puberty
Fulvestrant has been used in the treatment of peripheral precocious puberty in girls with McCune–Albright syndrome
McCune–Albright syndrome is a complex genetic disorder affecting the bone, skin and endocrine systems. It is a mosaic disease arising from somatic activating mutations in '' GNAS'', which encodes the alpha-subunit of the Gs heterotrimeric G ...
.
Available forms
Fulvestrant is provided in a castor oil
Castor oil is a vegetable oil pressed from castor beans, the seeds of the plant ''Ricinus communis''. The seeds are 40 to 60 percent oil. It is a colourless or pale yellow liquid with a distinct taste and odor. Its boiling point is and its den ...
solution
Solution may refer to:
* Solution (chemistry), a mixture where one substance is dissolved in another
* Solution (equation), in mathematics
** Numerical solution, in numerical analysis, approximate solutions within specified error bounds
* Solu ...
also containing alcohol
Alcohol may refer to:
Common uses
* Alcohol (chemistry), a class of compounds
* Ethanol, one of several alcohols, commonly known as alcohol in everyday life
** Alcohol (drug), intoxicant found in alcoholic beverages
** Alcoholic beverage, an alco ...
, benzyl alcohol
Benzyl alcohol (also known as α-cresol) is an aromatic alcohol with the formula C6H5CH2OH. The benzyl group is often abbreviated "Bn" (not to be confused with "Bz" which is used for benzoyl), thus benzyl alcohol is denoted as BnOH. Benzyl a ...
, and benzyl benzoate.
Contraindications
Fulvestrant should not be used in women with kidney failure
Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...
or who are pregnant
Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins.
Conception (biology), Conception usually occurs ...
.
Side effects
Very common (occurring in more than 10% of people) adverse effects include nausea, injection site reactions, weakness, and elevated transaminases
In medicine, the presence of elevated transaminases, commonly the transaminases alanine transaminase (ALT) and aspartate transaminase (AST), may be an indicator of liver dysfunction. Other terms include transaminasemia, and elevated liver enzym ...
. 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
Bilirubin (BR) (adopted from German, originally bili—bile—plus ruber—red—from Latin) is a red-orange compound that occurs in the normcomponent of the straw-yellow color in urine. Another breakdown product, stercobilin, causes the brown ...
, rashes, and back pain.[ In a large clinical trial, the incidence of ]venous thromboembolism
Venous thrombosis is the blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off ( embolizes) and flows to the lun ...
(VTE) with fulvestrant was 0.9%.
Pharmacology
Pharmacodynamics
Fulvestrant is an antiestrogen
Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inh ...
which acts as an antagonist
An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.[estrogen receptor
Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...](_b ...<br></span></div> of the <div class=)
(ER) and additionally as a selective estrogen receptor degrader (SERD).[ It works by binding to the estrogen receptor and making it more ]hydrophobic
In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, thu ...
, 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
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
of the G protein-coupled estrogen receptor (GPER), albeit with relatively low affinity (10–100 nM, relative to 3–6 nM for estradiol).
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.elimination half-life
Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...
of fulvestrant with intramuscular injection is 40 to 50 days.intravenous injection
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
, indicating that its long half-life with intramuscular injection is due to slow absorption from the injection site.loading dose
In pharmacokinetics, a loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose.
A loading dose is most useful for drugs that are eliminated from ...
on day 15 of therapy) in postmenopausal women with advanced breast cancer were 25.1 ng/mL (25,100 pg/mL) at peak Peak or The Peak may refer to:
Basic meanings Geology
* Mountain peak
** Pyramidal peak, a mountaintop that has been sculpted by erosion to form a point Mathematics
* Peak hour or rush hour, in traffic congestion
* Peak (geometry), an (''n''-3)-d ...
and 28.0 ng/mL (28,000 pg/mL) at trough
Trough may refer to:
In science
* Trough (geology), a long depression less steep than a trench
* Trough (meteorology), an elongated region of low atmospheric pressure
* Trough (physics), the lowest point on a wave
* Trough level (medicine), the l ...
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
In systems theory, a system or a process is in a steady state if the variables (called state variables) which define the behavior of the system or the process are unchanging in time. In continuous time, this means that for those properties ''p' ...
.blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...
in animals and may not in humans as well.brain
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
function have been observed in preclinical or clinical research
Clinical research is a branch of medical research that involves people and aims to determine the effectiveness (efficacy) and safety of medications, devices, diagnostic products, and treatment regimens intended for improving human health. The ...
.very low density lipoprotein
Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, low-density li ...
, low density lipoprotein
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
, and high density lipoprotein
High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are t ...
, but not to sex hormone-binding globulin
Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding prot ...
.metabolized
Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
along similar pathways as endogenous
Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell.
For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...
steroids; CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
may be involved, but non-cytochrome P450
Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
routes appear to be more important. It does not inhibit any cytochrome P450 enzymes. Elimination is almost all via feces.[
Fulvestrant can form ]colloid
A colloid is a mixture in which one substance consisting of microscopically dispersed insoluble particles is suspended throughout another substance. Some definitions specify that the particles must be dispersed in a liquid, while others exte ...
al aggregates at certain concentration ranges and this can limit its activity as well as produce bell-shaped concentration–response curves.
Chemistry
Fulvestrant, also known as 7α- -[(4,4,5,5,5-pentafluoropentyl)sulfinylonyl">4,4,5,5,5-pentafluoropentyl)sulfinyl.html" ;"title="-[(4,4,5,5,5-pentafluoropentyl)sulfinyl">-[(4,4,5,5,5-pentafluoropentyl)sulfinylonylstradiol, is a synthetic compound">synthetic
Synthetic may refer to:
Science
* Synthetic biology
* Synthetic chemical or compound, produced by the process of chemical synthesis
* Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...
estrane steroid and a chemical derivative, derivative of estradiol (medication), estradiol. An alkyl-sulfinyl moiety was added to the endogenous estrogen receptor ligand.