AROMASIN (exemestane) Action And Clinical Pharmacology

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Mechanism of Action:

Breast cancer cell growth is often estrogen-dependent and anti-tumour activity is expected following effective and continuous estrogen suppression in patients with hormone-sensitive breast cancer. Aromatase is the key 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 (mainly androstenedione) to estrogens (primarily estrone) by the aromatase enzyme in peripheral tissues. This occurs mainly in the adipose tissue, but also in the liver, muscle, hair follicles, and breast tissue. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for postmenopausal patients with hormone-dependent breast cancer.

AROMASIN (exemestane) is a potent aromatase inactivator, causing estrogen suppression and inhibition of peripheral aromatisation. It is a steroidal irreversible Type I aromatase inhibitor, structurally related to the natural substrate androstenedione. Exemestane is a specific competitive inactivator of human placental aromatase, which has been shown to be more potent than the irreversible aromatase inhibitor formestane or the reversible inhibitor aminoglutethimide in vitro.

In vivo studies of aromatase inactivation indicate that exemestane, by the oral route, is several times more potent than formestane. 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”. De novo aromatase enzyme synthesis is required for recovery of enzyme activity.  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.



Following oral administration of radiolabeled exemestane, at least 42% of radioactivity was absorbed from the gastrointestinal tract. Maximum exemestane plasma concentration (Cmax) was observed within 2 hours of receiving exemestane. Exemestane plasma levels increased by approximately 40% after a high-fat breakfast; however, no further effect on estrogen suppression was observed since maximum activity was already achieved under fasting conditions. Exemestane appears to be more rapidly absorbed in women with breast cancer than in healthy women.  After repeated doses, mean Tmax was 1.2 hours in the women with breast cancer and 2.9 hours in the healthy women. Mean AUC values following repeated doses were approximately 2-fold higher in women with breast cancer (75.4 ng.h/mL) compared with healthy women (41.4 ng.h/mL).  However, there was considerable overlap between the range of pharmacokinetic parameters observed in these two populations. 


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 α1-acid glycoprotein contribute equally to the binding. The distribution of exemestane and its metabolites into blood cells is negligible.

Metabolism and Excretion:

After reaching maximum plasma concentration, exemestane levels declined polyexponentially with a mean terminal half-life of about 24 hours.  Following administration of a single oral dose of radiolabeled exemestane, the elimination of drug-related products was essentially complete within 1 week. Approximately equal proportions of the dose were eliminated in urine and feces. The amount of drug excreted unchanged in urine was less than 1% of the dose, indicating that renal excretion is a limited elimination pathway. Exemestane was 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 demonstrate minimal ability to inhibit aromatase compared with the parent drug. Studies using human liver preparations indicate that cytochrome P-450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane. Additional studies in humans demonstrated that exemestane does not affect the activity of CYP3A4 to any great extent. No significant inhibition of any of the CYP isoenzymes (including CYP3A4) involved in xenobiotic metabolism was observed in human liver preparations. This would suggest that possible drug-drug interactions involving inhibition of CYP by co-administration with exemestane are unlikely.

Special Populations and Conditions:


Although women ranging in age up to 99 years were enrolled in the clinical studies (see WARNINGS AND PRECAUTIONS), healthy postmenopausal women aged 43 to 68 years were enrolled in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range.


The pharmacokinetics of exemestane following administration of a single, 25 mg tablet to fasted healthy males (mean age 32 years; range 19 to 51 years) or to fasted healthy postmenopausal women (mean age 55 years; range 45 to 68 years) have been compared. Mean Cmax and AUC values in healthy males (12.3 ± 5.8 ng/mL and 28.4 ± 17.3 ng.h/mL, respectively) were similar to those determined in healthy postmenopausal women (11.1 ± 4.4 ng/mL and 29.7 ± 7.8 ng.h/mL, respectively). Thus, the pharmacokinetics of exemestane does not appear to be influenced by gender.


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

Hepatic Insufficiency:

The pharmacokinetics of exemestane have been investigated in subjects with moderate and severe hepatic insufficiency. Following a single 25-mg oral dose, the AUC of exemestane was approximately 3 times higher than that observed in healthy volunteers. However no dosage adjustment is required for patients with liver impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended 25-mg daily dose (see WARNINGS AND PRECAUTIONS).

Renal Insufficiency:

The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with severe renal insufficiency (creatinine clearance <30 mL/min/1.73 m2) compared with the AUC in healthy volunteers.  However, no dosage adjustment is required for patients with renal impairment since exemestane was well tolerated in patients with breast cancer at doses 8 to 24 times higher than the recommended dose (see WARNINGS AND PRECAUTIONS).


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