Exemestane(Aromasin)

[Pheedno]

From RXList:

DESCRIPTION

AROMASIN Tablets for oral administration contain 25 mg of exemestane, an irreversible, steroidal aromatase inactivator. Exemestane is chemically described as 6-methylenandrosta-1,4-diene-3, 17-dione. Its molecular formula is C20H24O2.

The active ingredient is a white to slightly yellow crystalline powder with a molecular weight of 296.41. Exemestane is freely soluble in N, N-dimethylformamide, soluble in methanol, and practically insoluble in water.

Each AROMASIN Tablet contains the following inactive ingredients: mannitol, crospovidone, polysorbate 80, hydroxypropyl methylcellulose, colloidal silicon dioxide, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, simethicone, polyethylene glycol 6000, sucrose, magnesium carbonate, titanium dioxide, methylparaben, and polyvinyl alcohol.



CLINICAL PHARMACOLOGY

Mechanism of Action

Breast cancer cell growth may be estrogen-dependent. Aromatase (exemestane) is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone ) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer.

Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate 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.” Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.

Pharmacokinetics

Following oral administration to healthy postmenopausal women, exemestane is rapidly absorbed. After maximum plasma concentration is reached, levels decline polyexponentially with a mean terminal half-life of about 24 hours. Exemestane is extensively distributed and is cleared from the systemic circulation primarily by metabolism. The pharmacokinetics of exemestane are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50 mg). Following repeated daily doses of exemestane 25 mg, plasma concentrations of unchanged drug are similar to levels measured after a single dose.

Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following single or repeated doses have been compared with those in healthy, postmenopausal women. Exemestane appeared to be more rapidly absorbed in the women with breast cancer than in the healthy women, with a mean tmax of 1.2 hours in the women with breast cancer and 2.9 hours in the healthy women. After repeated dosing, the average oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 ng•h/mL) were about twice those in healthy women (41.4 ng•h/mL).

Absorption: Following oral administration of radiolabeled exemestane, at least 42% of radioactivity was absorbed from the gastrointestinal tract. Exemestane plasma levels increased by approximately 40% after a high-fat breakfast.

Distribution: Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and a1-acid glycoprotein both contribute to the binding. The distribution of exemestane and its metabolites into blood cells is negligible.

Metabolism and Excretion: Following administration of radiolabeled exemestane to healthy postmenopausal women, the cumulative amounts of radioactivity excreted in urine and feces were similar (42 ± 3% in urine and 42 ± 6% in feces over a 1-week collection period). The amount of drug excreted unchanged in urine was less than 1% of the dose.

Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity (see Pharmacodynamics: Other Endocrine Effects, below). Studies using human liver preparations indicate that cytochrome P450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane.

Special Populations

Geriatric: Healthy postmenopausal women aged 43 to 68 years were studied in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range.

Gender: The pharmacokinetics of exemestane following administration of a single, 25-mg tablet to fasted healthy males (mean age 32 years) were similar to the pharmacokinetics of exemestane in fasted healthy postmenopausal women (mean age 55 years).

Race: The influence of race on exemestane pharmacokinetics has not been evaluated.

Hepatic Insufficiency: The pharmacokinetics of exemestane have been investigated in subjects with moderate or severe hepatic insufficiency (Childs-Pugh B or C). Following a single 25-mg oral dose, the AUC of exemestane was approximately 3 times higher than that observed in healthy volunteers. (See PRECAUTIONS.)

Renal Insufficiency: The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with moderate or severe renal insufficiency (creatinine clearance <35 mL/min/1.73 m2 ) compared with the AUC in healthy volunteers (see PRECAUTIONS).

Pediatric: The pharmacokinetics of exemestane have not been studied in pediatric patients.

Drug-Drug Interactions

Exemestane is metabolized by cytochrome P450 3A4 (CYP 3A4) and aldoketoreductases. It does not inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1, and 3A4. In a clinical pharmacokinetic study, ketoconazole showed no significant influence on the pharmacokinetics of exemestane. Although no other formal drug-drug interaction studies have been conducted, significant effects on exemestane clearance by CYP isoenzymes inhibitors appear unlikely. However, a possible decrease of exemestane plasma levels by known inducers of CYP 3A4 cannot be excluded.

Pharmacodynamics

Effect on Estrogens: Multiple doses of exemestane ranging from 0.5 to 600 mg/day were administered to postmenopausal women with advanced breast cancer. Plasma estrogen (estradiol, estrone, and estrone sulfate) suppression was seen starting at a 5-mg daily dose of exemestane, with a maximum suppression of at least 85% to 95% achieved at a 25-mg dose. Exemestane 25 mg daily reduced whole body aromatization (as measured by injecting radiolabeled androstenedione) by 98% in postmenopausal women with breast cancer. After a single dose of exemestane 25 mg, the maximal suppression of circulating estrogens occurred 2 to 3 days after dosing and persisted for 4 to 5 days.

Effect on Corticosteroids: In multiple-dose trials of doses up to 200 mg daily, exemestane selectivity was assessed by examining its effect on adrenal steroids . Exemestane did not affect cortisol or aldosterone secretion at baseline or in response to ACTH at any dose. Thus, no glucocorticoid or mineralocorticoid replacement therapy is necessary with exemestane treatment.

Other Endocrine Effects: Exemestane does not bind significantly to steroidal receptors, except for a slight affinity for the androgen receptor (0.28% relative to dihydrotestosterone). The binding affinity of its 17-dihydrometabolite for the androgen receptor, however, is 100-times that of the parent compound. Daily doses of exemestane up to 25 mg had no significant effect on circulating levels of testosterone , androstenedione, dehydroepiandrosterone sulfate, or 17-hydroxy-progesterone. Increases in testosterone and androstenedione levels have been observed at daily doses of 200 mg or more. A dose- dependent decrease in sex hormone binding globulin (SHBG) has been observed with daily exemestane doses of 2.5 mg or higher. Slight, nondose-dependent increases in serum lutenizing hormone (LH) and follicle-stimulating hormone (FSH) levels have been observed even at low doses as a consequence of feedback at the pituitary level.


SIDE EFFECTS

A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. Exemestane was generally well tolerated, and adverse events were usually mild to moderate. Only one death was considered possibly related to treatment with exemestane; an 80-year-old women with known coronary artery disease had a myocardial infarction with multiple organ failure after 9 weeks on study treatment. In the clinical trials program, only 3% of the patients discontinued treatment with exemestane because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations because of adverse events were uncommon (0.3%).

DRUG INTERACTIONS

Exemestane is extensively metabolized by CYP 3A4, but coadministration of ketoconazole, a potent inhibitor of CYP 3A4, has no significant effect on exemestane pharmacokinetics. Significant pharmacokinetic interactions mediated by inhibition of CYP isoenzymes therefore appear unlikely; however, a possible decrease of exemestane plasma levels by known inducers of CYP 3A4 cannot be excluded

[einstein1905]

Pheedno,

You've mentioned that using tamoxifen with aromasin may not be necessary (for its positive estrogenic effects) due to the mechanism(s) of action of aromasin. Could you elaborate on that? I see aromatase being inhibited, whether it be competitive inhibition or inactivation (type II AIs or type I), as resulting in reduced estrogen. How would HDL not be adversely affected while using aromasin, which should suppress estrogen to a greater degree than the type IIs?
I'm probably overlooking something....this isn't really my area, but I've seen where you've mentioned that and I'm curious.

[Pheedno]

Well, I'm kind of torn on the matter. I've only seen one study which showed adverse effects to HDL with aromasin ; the study also showed adverse effects with letro, but none with anastrozole(I'll dig it up in a second). I've never used aromasin, so testing myself hasn't been an option at this point. I suppose a safe bet would be to run the maintenance dose of nolva, as the SERM isn't going hinder or hurt anything, but from everything I've read, it's effects to cholesterol are minor, if at all. Rather new in comparison to letro and anastrozole though. It's a med I've paid less attention to as it's not widely used in comparison to the other AI's
What I am really interested in, is the effects aromasin has on gonadotrophin concentrations for it's use in PCT. I have yet to find a study on it.

[Pheedno]

Yeah, heres a thread I posted back in October on the issue

http://anabolicreview.com/vbulletin/...light=Aromasin

[einstein1905]

From the full text of the following study, which was 56 total days of exemestane in doses ranging from 0.5-5mg QD, it showed roughly 40% increases in both FSH and LH after 28 days at 2.5mg/day.....not bad.


Eur J Cancer. 1997 Apr;33(4):587-91. Related Articles, Links


The minimal effective exemestane dose for endocrine activity in advanced breast cancer.

Bajetta E, Zilembo N, Noberasco C, Martinetti A, Mariani L, Ferrari L, Buzzoni R, Greco M, Bartoli C, Spagnoli I, Danesini GM, Artale S, Paolini J.

Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

Phase I studies have demonstrated that exemestane, an irreversible oral aromatase inhibitor, is able to suppress circulating oestrogen levels. In our previous experience, doses ranging from 2.5 to 25 mg induced a similar suppression of oestrogens. The aim of this study was to identify the minimum effective exemestane dose on the basis of endocrine activity. 20 evaluable postmenopausal advanced breast cancer patients were randomly given exemestane 0.5, 1, 2.5 or 5 mg, in double-blind conditions. Oestrone (E1), oestradiol (E2), oestrone sulphate (E1S), gonadotrophins, sex-hormone binding globulin and dehydroepiandrosterone sulphate serum levels were evaluated from the first day of treatment to the 7th, 14th, 28th and 56th day. Serum E1, E2 and E1S levels were suppressed by all doses starting from day 7; the degree of inhibition versus baseline was 25 up to 72% for E1, 30 up to 62% for E2 and 16 up to 52% for E1S, with higher doses achieving greater suppression; these changes were maintained over time. A significant increase in FSH and LH levels was observed for all doses. Treatment tolerability was satisfactory. The endocrine effects of exemestane appear to be dose related and 0.5 and 1 mg are ineffective for adequately suppressing circulating oestrogens.

[einstein1905]

Eur J Cancer. 1991;27(9):1145-50. Related Articles, Links


Comparison of the effects of the irreversible aromatase inhibitor exemestane with atamestane and MDL 18962 in rats with DMBA-induced mammary tumours.

Zaccheo T, Giudici D, Ornati G, Panzeri A, di Salle E.

Oncology Line, Research and Development, Farmitalia Carlo Erba, Erbamont Group, Milan, Italy.

The antitumour activity of the steroidal aromatase inhibitors exemestane (FCE 24304), MDL 18962 and atamestane (SH 489) was evaluated on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumours in rats. The compounds were given subcutaneously at daily doses of 10 and 50 mg/kg for 4 weeks. Exemestane was also given orally, at daily doses of 100 and 200 mg/kg. Subcutaneous exemestane induced 30% (10 mg/kg) and 73% (50 mg/kg) regressions of established tumours and strongly reduced the appearance of new tumours. Conversely, atamestane, MDL 18962 and oral exemestane did not affect growth of established tumours nor influenced the appearance of new neoplasms. Aromatase activity of ovarian microsomes (OAA) was reduced by 85%-93% after subcutaneous exemestane and by 25%-59% after MDL 18962, and was unaffected after atamestane. Oral exemestane caused a reduction in OAA of 72%-74%. Serum luteinising hormone (LH) levels were reduced at both the subcutaneous doses of exemestane and at the higher dose of MDL 18962. Atamestane caused an increase in LH levels, while no effect was observed with oral exemestane. The LH-lowering effect of subcutaneous exemestane, the less marked effect of MDL 18962, and the ineffectiveness of oral exemestane were also observed after 10 days of treatment in ovariectomised rats. The antigonadotrophic effect of subcutaneous exemestane, which is probably due to its slight androgenic effect, could contribute to its antitumour activity in the DMBA tumour model in intact rats, through a counteraction of the negative feedback of oestrogens on gonadotropin secretion.

This makes sense....it's very androstenedione-like

[einstein1905]

J Steroid Biochem Mol Biol. 1992 Sep;43(1-3):137-43. Related Articles, Links


Exemestane (FCE 24304), a new steroidal aromatase inhibitor.

di Salle E, Ornati G, Giudici D, Lassus M, Evans TR, Coombes RC.

Oncology Line, Research and Development, Nerviano (Mi), Italy.

Exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17-dione) is a novel orally active irreversible aromatase inhibitor. Its in vitro and in vivo pharmacological properties have been compared to 4-hydroxyandrostenedione (4-OHA). In preincubation studies with human placental aromatase, exemestane, like 4-OHA, showed enzyme inactivating properties with a similar affinity (Ki 26 vs 29 nM) and a lower rate of inactivation (t1/2 13.9 vs 2.1 min). Conversely, when tested in pregnant mares' serum gonadotropin-treated rats, exemestane was more potent in reducing microsomal ovarian aromatase activity than 4-OHA, after both subcutaneous (ED50 1.8 vs 3.1 mg/kg) and oral dosing (ED50 3.7 vs greater than 100 mg/kg). No interference of exemestane on desmolase or 5 alpha-reductase activity was found. The compound did not show any relevant binding affinity to steroidal receptors, but slight binding to the androgen receptor (approximately 0.2% of dihydrotestosterone), like 4-OHA. In the first phase I trial, healthy postmenopausal volunteers were given single oral doses of exemestane, ranging from 0.5 to 800 mg, and plasma [estrone (E1), estradiol (E2) and estrone sulphate (E1S)] and urinary estrogens (E1 and E2) were measured up to 5-8 days. The minimal effective dose in decreasing estrogens was 5 mg. At 25 mg the maximal suppression was observed at day 3: plasma estrogens fell to 35 (E1), 39 (E2) and 28% (E1S), and urinary estrogens fell to 20 (E1) and 25% (E2) of basal values, these effects still persisting on day 5. No effects on plasma levels of cortisol, aldosterone, 17-hydroxyprogesterone, DHEAS, LH and FSH, and no significant adverse events were observed up to the highest tested dose of 800 mg exemestane.

[flexshack]

einstein, why is part of the first study you posted contradicting a part of the third study. the part about lh and fsh being raised substantially in one while not effected in another study.
the delivery method was different for the middle one so i am not comparing it.

[einstein1905]

einstein, why is part of the first study you posted contradicting a part of the third study. the part about lh and fsh being raised substantially in one while not effected in another study.
the delivery method was different for the middle one so i am not comparing it.

Welcome to the world of science. Not all conclusions are Llewellynesque
It's very common to find studies which contradict eachother. The challenge is to try and sniff out exactly what may have been different in one study versus the other....and sometimes, there just is not an explanation.
The 2nd study is just as valid as the other 2 IMO, the route of delivery shouldn't make much difference here...other than magnitude of effects (possibly), but the same trends should be seen. The 2nd study does give a reasonable conclusion IMO. Aromasin is very similar to androstendione, so it may be seen as an androgen in the body and feedback to attenuate further endogenous androgen production. If only I had never seen the latter 2 studies, I'd be pretty happy with the results of the first alone.

[Pheedno]

Welcome to the world of science. Not all conclusions are Llewellynesque .

It's very common to find studies which contradict eachother. The challenge is to try and sniff out exactly what may have been different in one study versus the other....and sometimes, there just is not an explanation.
The 2nd study is just as valid as the other 2 IMO, the route of delivery shouldn't make much difference here...other than magnitude of effects (possibly), but the same trends should be seen. The 2nd study does give a reasonable conclusion IMO. Aromasin is very similar to androstendione, so it may be seen as an androgen in the body and feedback to attenuate further endogenous androgen production. If only I had never seen the latter 2 studies, I'd be pretty happy with the results of the first alone.

I agree, difinitive conclusions based on studies are not easy to come by as a dozen contradicts a dozen. Consideration has to be given to duration, number of patients(which are often a very small number), doses(in comaprison to our use), and what ever other variable you can pick out of a certain study that might have an effect.
In this case, I think it's safe to run the nolva. A "just in case" administration. Once I finish up my stock of L-dex, I'm going to switch over to exemestane so I can see it in my own blood work, with and without nolva

[flexshack]

Welcome to the world of science. Not all conclusions are Llewellynesque

i like that, lol.

It's very common to find studies which contradict eachother. The challenge is to try and sniff out exactly what may have been different in one study versus the other....and sometimes, there just is not an explanation.
The 2nd study is just as valid as the other 2 IMO, the route of delivery shouldn't make much difference here...other than magnitude of effects (possibly), but the same trends should be seen. The 2nd study does give a reasonable conclusion IMO. Aromasin is very similar to androstendione, so it may be seen as an androgen in the body and feedback to attenuate further endogenous androgen production. If only I had never seen the latter 2 studies, I'd be pretty happy with the results of the first alone.

and there are always idiosyncrasies too, right?