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| Pronunciation | /ˌɛksəˈmɛˌsteɪn/ EK-sə-ME-stayn |
| Trade names | Aromasin |
| Other names | FCE-24304 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a607006 |
| Routes of administration | By mouth |
| Drug class | Aromatase inhibitor;Antiestrogen |
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| Pharmacokinetic data | |
| Bioavailability | ~60%[citation needed] |
| Protein binding | 90% |
| Metabolism | Liver (CYP3A4,aldo-keto reductase) |
| Eliminationhalf-life | 24 hours |
| Duration of action | 4–5 days[citation needed] |
| Excretion | Urine and feces ~ 1:1 (mainly metabolites) |
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| ECHA InfoCard | 100.171.149 |
| Chemical and physical data | |
| Formula | C20H24O2 |
| Molar mass | 296.410 g·mol−1 |
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Exemestane, sold under the brand nameAromasin among others, is amedication used to treatbreast cancer. It is a member of the class ofantiestrogens known asaromatase inhibitors. Some breast cancers requireestrogen to grow. Those cancers have estrogenreceptors (ERs), and are called ER-positive. They may also be called estrogen-responsive, hormonally-responsive, or hormone-receptor-positive.Aromatase is anenzyme that synthesizes estrogen. Aromatase inhibitors block the synthesis of estrogen. This lowers the estrogen level, and slows the growth of cancers.
Exemestane isindicated for theadjuvant treatment ofpostmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years oftamoxifen and are switched to it for completion of a total of five consecutive years of adjuvant hormonal therapy.[3]US FDA approval was in October 1999.[4]
Exemestane is also indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.[5]
For premenopausal women with hormone-receptor–positive breast cancer, adjuvant treatment with ovarian suppression plus the aromatase inhibitor exemestane, as compared with ovarian suppression plus tamoxifen, provides a new treatment option that reduces the risk of recurrence. The TEXT and SOFT trials demonstrated improved disease free survival in patients treated with exemestane and ovarian suppression compared to the tamoxifen and ovarian suppression group. Premenopausal women who receive ovarian suppression may now benefit from an aromatase inhibitor, a class of drugs that until now has been recommended only for postmenopausal women.[6]
The drug is contraindicated inpremenopausal women, which of course includes pregnant andlactating women.[7]
The most common side effects (more than 10% of patients) arehot flashes and sweating, which are typical of estrogen deficiency as caused by exemestane, and alsoinsomnia, headache, andjoint pain. Nausea andfatigue are mainly observed in patients with advanced breast cancer.[7][8]
An occasional decrease in lymphocytes has been observed in approximately 20% of patients receiving Aromasin, particularly in patients with pre-existing lymphopenia.[9]
Exemestane hasandrogenic properties similarly toformestane and can produce androgenic side effects such asacne andweight gain, although these are generally associated with supratherapeutic dosages of the drug.[10]
Single doses of up to at least 32-fold (800 mg), as well as continuous therapy with 24-fold (600 mg) the usual daily dose are well tolerated. No life-threatening overdosing is known in humans, but only in animal studies with 2000- to 4000-fold doses (adjusted tobody surface area).[7]
Exemestane is metabolized by the liver enzymeCYP3A4. While the CYP3A4 inhibitorketoconazole had no significant effect on exemestane levels in a clinical trial, the strong CYP3A4 inductorrifampicin significantly cut exemestane levels about in half (AUC −54%,Cmax −41% for a single dose), potentially compromising its effectiveness. Other 3A4 inductors such ascarbamazepine andSt John's Wort are expected to have similar effects.[7][8] The clinical relevance of this effect has not been investigated.[11]
Estrogens probably reduce exemestane effectiveness:[8] It would usually be counter-productive to reduce the body's estrogen synthesis with exemestane and then substitute estrogen with pharmaceuticals.
Exemestane is an oral steroidal aromatase inhibitor that is used in ER-positive breast cancer in addition to surgery and/or radiation in post-menopausal women.
The main source ofestrogen is the ovaries in premenopausal women, while in post-menopausal women most of the body's estrogen is produced via the conversion ofandrogens into estrogen by the aromatase enzyme in the peripheral tissues (i.e. adipose tissue like that of the breast) and a number of sites in the brain. Estrogen is produced locally via the actions of the aromatase enzyme in these peripheral tissues where it acts locally. Any circulating estrogen in post-menopausal women as well as men is the result of estrogen escaping local metabolism and entering the circulatory system.[12]
Exemestane is an irreversible, steroidal aromatase inactivator of type I, structurally related to the natural substrate4-androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as "suicide inhibition." By being structurally similar to enzyme targets, exemestane permanently binds to the enzymes, preventing them from converting androgen into estrogen.[7]
Type II aromatase inhibitors such asanastrozole andletrozole, by contrast, are not steroids and work by interfering with the aromatase'sheme.[11]
A study conducted on young adult males found that the estrogen suppression rate for exemestane varied from 35% forestradiol (E2) to 70% forestrone (E1).[13]
| Generation | Medication | Dosage | % inhibitiona | Classb | IC50c |
|---|---|---|---|---|---|
| First | Testolactone | 250 mg 4x/dayp.o. | ? | Type I | ? |
| 100 mg 3x/weeki.m. | ? | ||||
| Rogletimide | 200 mg 2x/dayp.o. 400 mg 2x/dayp.o. 800 mg 2x/dayp.o. | 50.6% 63.5% 73.8% | Type II | ? | |
| Aminoglutethimide | 250 mg mg 4x/dayp.o. | 90.6% | Type II | 4,500 nM | |
| Second | Formestane | 125 mg 1x/dayp.o. 125 mg 2x/dayp.o. 250 mg 1x/dayp.o. | 72.3% 70.0% 57.3% | Type I | 30 nM |
| 250 mg 1x/2 weeksi.m. 500 mg 1x/2 weeksi.m. 500 mg 1x/1 weeki.m. | 84.8% 91.9% 92.5% | ||||
| Fadrozole | 1 mg 1x/dayp.o. 2 mg 2x/dayp.o. | 82.4% 92.6% | Type II | ? | |
| Third | Exemestane | 25 mg 1x/dayp.o. | 97.9% | Type I | 15 nM |
| Anastrozole | 1 mg 1x/dayp.o. 10 mg 1x/dayp.o. | 96.7–97.3% 98.1% | Type II | 10 nM | |
| Letrozole | 0.5 mg 1x/dayp.o. 2.5 mg 1x/dayp.o. | 98.4% 98.9%–>99.1% | Type II | 2.5 nM | |
| Footnotes:a = Inpostmenopausal women.b = Type I:Steroidal,irreversible (substrate-binding site). Type II:Nonsteroidal,reversible (binding to and interference with thecytochrome P450hememoiety).c = Inbreast cancerhomogenates.Sources: See template. | |||||
Exemestane is quickly absorbed from the gut, but undergoes a strongfirst-pass effect in the liver. Highest blood plasma concentrations are reached after 1.2 hours in breast cancer patients and after 2.9 hours in healthy subjects. Maximal aromatase inhibition occurs after two to three days.[11] 90% of the absorbed substance are bound toplasma proteins. The liver enzyme CYP3A4oxidizes themethylidene group in position 6, and the 17-keto group (on the five-membered ring) is reduced byaldo-keto reductases to analcohol. Of the resulting metabolites, 40% are excreted via the urine and 40% via the feces within a week. The original substance accounts for only 1% of excretion in the urine. The terminal half-life is 24 hours.[7][14]
Exemestane is known chemically as 6-methylideneandrosta-1,4-diene-3,17-dione. Like the aromatase inhibitorsformestane andatamestane, exemestane is asteroid that is structurally similar to 4-androstenedione, the natural substrate of aromatase. It is distinguished from the natural substance only by the methylidene group in position 6 and an additional double bond in position 1.[15]
Pure exemestane is a white to off-white powder that is soluble inDMSO to at least 20 mg/mL.Optical rotation [α]D is +250 to 300° (per g/100 cm3 and decimetre at 589 nm wavelength).[16]
Exemestane has been used indoping to raiseluteinizing hormone (LH) andfollicle stimulating hormone (FSH) levels, which in turn increases the ratio of male over female sexual hormones and so improves performance. The drug also counteractsgynecomastia as well as fat andwater retention following excessive aromatase production due totestosterone doping.[17] It is also used by steroid users to lower female sexual horomone levels following a cycle of steroids, often called a "post-cycle therapy", it is also used alongsideSelective estrogen receptor modulators in this.
Rarely, it is used recreationally by teenagers to delay epiphyseal plate closure and increase adult height, particularly among members of theLooksmaxxing andincel communities, where its use is documented on their forums.[18][19] However, its effectiveness for this purpose is debatable.
Along with other aromatase inhibitors, exemestane is on theWorld Anti-Doping Agency's list of prohibited substances.[20]
Oral exemestane 25 mg/day for 2–3 years of adjuvant therapy was generally more effective than 5 years of continuous adjuvanttamoxifen in the treatment of postmenopausal women with early-stage estrogen receptor-positive/unknown receptor status breast in a large well-designed[citation needed] trial. Preliminary data from the open-label TEAM trial comparing exemestane with tamoxifen indicated in 2009 that exemestane 25 mg/day is also effective in the primary adjuvant treatment of early-stage breast cancer in postmenopausal women.[21]
Interim phase III trial results in 2011 showed that addingeverolimus to exemestane therapy against advanced breast cancer can significantly improveprogression-free survival compared with exemestane therapy alone.[22]
A Phase III trial was reported in 2011, concluding that the use of exemestane in postmenopausal women at an increased risk for breast cancer reduced the incidence of invasive breast cancer. In 4,560 women, after 35 months, the administration of exemestane at a dose of 25 mg/day resulted in a 65% reduction in the risk of breast cancer compared with placebo; annual incidence rates were 0.19% and 0.55%, respectively (hazard ratio: 0.35; 95% CI [0.18-0.70]; p = 0.002).[23]