Anastrozole

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Anastrozole
Anastrozole.svg
Anastrozole-from-xtal-3D-balls.png
Clinical data
Trade names Arimidex, Aremed, others [1]
Other namesAnastrazole; anastrozol; ICI-D1033; ZD-1033
AHFS/Drugs.com Monograph
MedlinePlus a696018
License data
Pregnancy
category
  • AU:C
Routes of
administration 		By mouth
Drug class Aromatase inhibitor; Antiestrogen
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability Unknown (but well-absorbed in animals) [2]
Protein binding 40% [3] [4]
Metabolism Liver (~85%) (N-dealkylation, hydroxylation, glucuronidation) [3] [2] [4]
Elimination half-life 40–50 hours [3] [2] [4]
Excretion Urine (11%) [3] [2] [4]
Identifiers
  • 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methylpropanenitrile) [5]
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.129.723 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H19N5
Molar mass 293.374 g·mol−1
3D model (JSmol)
  • N#CC(C)(C)c1cc(Cn2cncn2)cc(c1)C(C)(C)C#N
  • InChI=1S/C17H19N5/c1-16(2,9-18)14-5-13(8-22-12-20-11-21-22)6-15(7-14)17(3,4)10-19/h5-7,11-12H,8H2,1-4H3 Yes check.svgY
  • Key:YBBLVLTVTVSKRW-UHFFFAOYSA-N Yes check.svgY
   (verify)

Anastrozole, sold under the brand name Arimidex among others, is an antiestrogenic medication used in addition to other treatments for breast cancer. [6] [7] Specifically it is used for hormone receptor-positive breast cancer. [7] It has also been used to prevent breast cancer in those at high risk. [7] It is taken by mouth. [7]

Contents

Common side effects of anastrozole include hot flashes, altered mood, joint pain, and nausea. [7] [6] Severe side effects include an increased risk of heart disease and osteoporosis. [7] Use during pregnancy may harm the baby. [7] Anastrozole is in the aromatase-inhibiting family of medications. [7] It works by blocking the production of estrogens in the body, and hence has antiestrogenic effects. [7]

Anastrozole was patented in 1987 and was approved for medical use in 1995. [8] [9] It is on the World Health Organization's List of Essential Medicines. [10] Anastrozole is available as a generic medication. [7] In 2020, it was the 180th most commonly prescribed medication in the United States, with more than 3 million prescriptions. [11] [12]

Medical uses

Breast cancer

Anastrozole is used in the treatment and prevention of breast cancer in women. [7] The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was of localized breast cancer and women received either anastrozole, the selective estrogen receptor modulator tamoxifen, or both for five years, followed by five years of follow-up. [13] After more than 5 years the group that received anastrozole had better results than the tamoxifen group. [13] The trial suggested that anastrozole is the preferred medical therapy for postmenopausal women with localized estrogen receptor-positive breast cancer. [13]

Early puberty

Anastrozole is used at a dosage of 0.5 to 1 mg/day in combination with the antiandrogen bicalutamide in the treatment of peripheral precocious puberty, for instance due to familial male-limited precocious puberty (testotoxicosis) and McCune–Albright syndrome, in boys. [14] [15] [16] [17] [18] [19] [20] [21] [22] [23]

Available forms

Anastrozole is available in the form of 1 mg oral tablets. [6] [24] No alternative forms or routes are available. [24]

Contraindications

Contraindications of anastrozole include hypersensitivity to anastrozole or any other component of anastrozole formulations, pregnancy, and breastfeeding. [6] Hypersensitivity reactions to anastrozole including anaphylaxis, angioedema, and urticaria have been observed. [6]

Side effects

Common side effects of anastrozole (≥10% incidence) include hot flashes, asthenia, arthritis, pain, arthralgia, hypertension, depression, nausea and vomiting, rash, osteoporosis, bone fractures, back pain, insomnia, headache, bone pain, peripheral edema, coughing, dyspnea, pharyngitis, and lymphedema. [6] Serious but rare adverse effects (<0.1% incidence) include skin reactions such as lesions, ulcers, or blisters; allergic reactions with swelling of the face, lips, tongue, and/or throat that may cause difficulty swallowing or breathing; and abnormal liver function tests as well as hepatitis. [6]

Interactions

Anastrozole is thought to have clinically negligible inhibitory effects on the cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2D6, CYP2C8, CYP2C9, and CYP2C19. [3] [2] [4] [6] As a result, it is thought that drug interactions of anastrozole with cytochrome P450 substrates are unlikely. [4] No clinically significant drug interactions have been reported with anastrozole as of 2003. [3]

Anastrozole does not affect circulating levels of tamoxifen or its major metabolite N-desmethyltamoxifen. [3] [2] However, tamoxifen has been found to decrease steady-state area-under-the-curve levels of anastrozole by 27%. [3] [2] But estradiol levels were not significantly different in the group that received both anastrozole and tamoxifen compared to the anastrozole alone group, so the decrease in anastrozole levels is not thought to be clinically important. [4]

Pharmacology

Pharmacodynamics

Anastrozole works by reversibly binding to the aromatase enzyme, and through competitive inhibition blocks the conversion of androgens to estrogens in peripheral (extragonadal) tissues. [25] The medication has been found to achieve 96.7% to 97.3% inhibition of aromatase at a dosage of 1 mg/day and 98.1% inhibition of aromatase at a dosage of 10 mg/day in humans. [3] [2] As such, 1 mg/day is considered to be the minimal dosage required to achieve maximal suppression of aromatase with anastrozole. [3] This decrease in aromatase activity results in an at least 85% decrease in estradiol levels in postmenopausal women. [3] Levels of corticosteroids and other adrenal steroids are unaffected by anastrozole. [3]

Pharmacodynamics of aromatase inhibitors
GenerationMedicationDosage % inhibitionaClassbIC50c
First Testolactone 250 mg 4x/day p.o. ?Type I ?
100 mg 3x/week i.m. ?
Rogletimide 200 mg 2x/day p.o.
400 mg 2x/day p.o.
800 mg 2x/day p.o.		50.6%
63.5%
73.8%		Type II ?
Aminoglutethimide 250 mg mg 4x/day p.o.90.6%Type II4,500 nM
Second Formestane 125 mg 1x/day p.o.
125 mg 2x/day p.o.
250 mg 1x/day p.o.		72.3%
70.0%
57.3%		Type I30 nM
250 mg 1x/2 weeks i.m.
500 mg 1x/2 weeks i.m.
500 mg 1x/1 week i.m.		84.8%
91.9%
92.5%
Fadrozole 1 mg 1x/day p.o.
2 mg 2x/day p.o.		82.4%
92.6%		Type II ?
Third Exemestane 25 mg 1x/day p.o.97.9%Type I15 nM
Anastrozole1 mg 1x/day p.o.
10 mg 1x/day p.o.		96.7–97.3%
98.1%		Type II10 nM
Letrozole 0.5 mg 1x/day p.o.
2.5 mg 1x/day p.o.		98.4%
98.9%–>99.1%		Type II2.5 nM
Footnotes:a = In postmenopausal women. b = Type I: Steroidal, irreversible (substrate-binding site). Type II: Nonsteroidal, reversible (binding to and interference with the cytochrome P450 heme moiety). c = In breast cancer homogenates. Sources: See template.

Pharmacokinetics

The bioavailability of anastrozole in humans is unknown, but it was found to be well-absorbed in animals. [2] [6] Absorption of anastrozole is linear over a dosage range of 1 to 20 mg/day in humans and does not change with repeated administration. [3] [4] [6] Food does not significantly influence the extent of absorption of anastrozole. [4] [6] Peak levels of anastrozole occur a median 3 hours after administration, but with a wide range of 2 to 12 hours. [2] [4] Steady-state levels of anastrozole are achieved within 7 to 10 days of continuous administration, with 3.5-fold accumulation. [3] [2] [4] However, maximal suppression of estradiol levels occurs within 3 or 4 days of therapy. [3]

Active efflux of anastrozole by P-glycoprotein at the blood–brain barrier has been found to limit the central nervous system penetration of anastrozole in rodents, whereas this was not the case with letrozole and vorozole. [26] [27] [28] As such, anastrozole may have peripheral selectivity in humans, although this has yet to be confirmed. [28] In any case, estradiol is synthesized peripherally and readily crosses the blood–brain barrier, so anastrozole would still expected to reduce estradiol levels in the central nervous system to a certain degree. The plasma protein binding of anastrozole is 40%. [3] [4]

The metabolism of anastrozole is by N-dealkylation, hydroxylation, and glucuronidation. [3] Inhibition of aromatase is due to anastrozole itself rather than to metabolites, with the major circulating metabolite being inactive. [6] The elimination half-life of anastrozole is 40 to 50 hours (1.7 to 2.1 days). [3] [2] [4] This allows for convenient once-daily administration. [4] The medication is eliminated predominantly by metabolism in the liver (83 to 85%) but also by residual excretion by the kidneys unchanged (11%). [3] [2] [4] Anastrozole is excreted primarily in urine but also to a lesser extent in feces. [4]

Chemistry

Anastrozole is a nonsteroidal benzyl triazole. [3] [4] It is also known as α,α,α',α'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-m-benzenediacetonitrile. [1] Anastrozole is structurally related to letrozole, fadrozole, and vorozole, with all being classified as azoles. [29] [30] [31] [32]

History

Anastrozole was patented by Imperial Chemical Industries (ICI) in 1987 and was approved for medical use, specifically the treatment of breast cancer, in 1995. [8] [9]

Society and culture

Generic names

Anastrozole is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, BAN Tooltip British Approved Name, and JAN Tooltip Japanese Accepted Name. [1]

Brand names

Anastrozole is primarily sold under the brand name Arimidex. [1] However, it is also marketed under a variety of other brand names throughout the world. [1]

Availability

Anastrozole is available widely throughout the world. [1]

Research

Anastrozole is surprisingly ineffective at treating gynecomastia, in contrast to selective estrogen receptor modulators like tamoxifen. [33] [34]

Anastrozole was under development for the treatment of female infertility but did not complete development and hence was never approved for this indication. [35]

An anastrozole and levonorgestrel vaginal ring (developmental code name BAY 98–7196) was under development for use as a hormonal contraceptive and treatment for endometriosis, but development was discontinued in November 2018 and the formulation was never marketed. [36]

Anastrozole increases testosterone levels in males and has been studied as an alternative method of androgen replacement therapy in men with hypogonadism. [37] [38] However, there are concerns about its long-term influence on bone mineral density in this patient population, as well as other adverse effects. [37]

Related Research Articles

<span class="mw-page-title-main">Estradiol</span> Chemical compound

Estradiol (E2), also spelled 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 for the development of female secondary sexual characteristics such as the breasts, widening of the hips and a female-associated pattern of fat distribution. It is also important in the development and maintenance of female reproductive tissues such as the mammary glands, uterus and vagina during puberty, adulthood and pregnancy. It also has important effects in many other tissues including bone, fat, skin, liver, and the brain.

<span class="mw-page-title-main">Tamoxifen</span> Medication

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.

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.

<span class="mw-page-title-main">Aromatase inhibitor</span> Class of drugs

Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone exogenously. They may also be used for chemoprevention in women at high risk for breast cancer.

<span class="mw-page-title-main">Raloxifene</span> Chemical compound

Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to reduce the risk of breast cancer in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Estradiol acetate</span> Chemical compound

Estradiol acetate (EA), sold under the brand names Femtrace, Femring, and Menoring, is an estrogen medication which is used in hormone therapy for the treatment of menopausal symptoms in women. It is taken by mouth once daily or given as a vaginal ring once every three months.

<span class="mw-page-title-main">Letrozole</span> Breast cancer drug

Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer.

<span class="mw-page-title-main">Exemestane</span> Breast cancer medication

Exemestane, sold under the brand name Aromasin among others, is a medication used to treat breast cancer. It is a member of the class of antiestrogens known as aromatase inhibitors. Some breast cancers require estrogen to grow. Those cancers have estrogen receptors (ERs), and are called ER-positive. They may also be called estrogen-responsive, hormonally-responsive, or hormone-receptor-positive. Aromatase is an enzyme that synthesizes estrogen. Aromatase inhibitors block the synthesis of estrogen. This lowers the estrogen level, and slows the growth of cancers.

<span class="mw-page-title-main">Tibolone</span> Chemical compound

Tibolone, sold under the brand name Livial among others, is a medication which is used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis. The medication is available alone and is not formulated or used in combination with other medications. It is taken by mouth.

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 inhibiting or suppressing estrogen production. Antiestrogens are one of three types of sex hormone antagonists, the others being antiandrogens and antiprogestogens. Antiestrogens are commonly used to stop steroid hormones, estrogen, from binding to the estrogen receptors leading to the decrease of estrogen levels. Decreased levels of estrogen can lead to complications in sexual development. Antiandrogens are sex hormone antagonists which are able to lower the production and the effects that testosterone can have on female bodies.

<span class="mw-page-title-main">Testolactone</span> Chemical compound

Testolactone is a non-selective, irreversible, steroidal aromatase inhibitor which is used as an antineoplastic drug to treat advanced-stage breast cancer. The drug was discontinued in 2008 and is no longer available for medical use.

<span class="mw-page-title-main">Estrone sulfate</span> Chemical compound

Estrone sulfate, also known as E1S, E1SO4 and estrone 3-sulfate, is a natural, endogenous steroid and an estrogen ester and conjugate.

<span class="mw-page-title-main">Estradiol cypionate</span> Chemical compound

Estradiol cypionate (EC), sold under the brand name Depo-Estradiol among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for trans women, and in hormonal birth control for women. It is given by injection into muscle once every 1 to 4 weeks.

<span class="mw-page-title-main">Aromatase excess syndrome</span> Medical condition

Aromatase excess syndrome is a rarely diagnosed genetic and endocrine syndrome which is characterized by an overexpression of aromatase, the enzyme responsible for the biosynthesis of the estrogen sex hormones from the androgens, in turn resulting in excessive levels of circulating estrogens and, accordingly, symptoms of hyperestrogenism. It affects both sexes, manifesting itself in males as marked or complete phenotypical feminization and in females as hyperfeminization.

<span class="mw-page-title-main">Gynecomastia</span> Endocrine system disorder of human male breast

Gynecomastia is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Gynecomastia can cause significant psychological distress or unease.

An estrogen-dependent condition can be that relating to the differentiation in the steroid sex hormone that is associated with the female reproductive system and sex characteristics. These conditions can fall under the umbrella of hypoestrogenism, hyperestrogenim, or any sensitivity to the presence of estrogen in the body.

<span class="mw-page-title-main">Conjugated estrogens</span> Estrogen medication

Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the sodium salts of estrogen conjugates found in horses, such as estrone sulfate and equilin sulfate. CEEs are available in the form of both natural preparations manufactured from the urine of pregnant mares and fully synthetic replications of the natural preparations. They are formulated both alone and in combination with progestins such as medroxyprogesterone acetate. CEEs are usually taken by mouth, but can also be given by application to the skin or vagina as a cream or by injection into a blood vessel or muscle.

<span class="mw-page-title-main">High-dose estrogen therapy</span> Type of hormone therapy

High-dose estrogen therapy (HDE) is a type of hormone therapy in which high doses of estrogens are given. When given in combination with a high dose of progestogen, it has been referred to as pseudopregnancy. It is called this because the estrogen and progestogen levels achieved are in the range of the very high levels of these hormones that occur during pregnancy. HDE and pseudopregnancy have been used in medicine for a number of hormone-dependent indications, such as breast cancer, prostate cancer, and endometriosis, among others. Both natural or bioidentical estrogens and synthetic estrogens have been used and both oral and parenteral routes may be used.

The medical uses of bicalutamide, a nonsteroidal antiandrogen (NSAA), include the treatment of androgen-dependent conditions and hormone therapy to block the effects of androgens. Indications for bicalutamide include the treatment of prostate cancer in men, skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women, high testosterone levels in women, hormone therapy in transgender women, as a puberty blocker to prevent puberty in transgender girls and to treat early puberty in boys, and the treatment of long-lasting erections in men. It may also have some value in the treatment of paraphilias and hypersexuality in men.

<span class="mw-page-title-main">Pharmacokinetics of estradiol</span>

The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

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  36. ↑ "Anastrozole/levonorgestrel intravaginal ring - Bayer HealthCare". Adis Insight.
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  38. ↑ Khera M, Adaikan G, Buvat J, Carrier S, El-Meliegy A, Hatzimouratidis K, et al. (December 2016). "Diagnosis and Treatment of Testosterone Deficiency: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015)". The Journal of Sexual Medicine. 13 (12): 1787–1804. doi:10.1016/j.jsxm.2016.10.009. PMID   27914560.
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