Exemestane - How It Works
Clinical pharmacology details from the US FDA-approved label: how Exemestane works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Breast cancer cell growth may be estrogen-dependent. Aromatase 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. 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 adren
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Breast cancer cell growth may be estrogen-dependent.
Aromatase 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.
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.
12.2 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 androstenedione, dehydroepiandrosterone sulfate, or 17-hydroxyprogesterone, and were associated with small decreases in circulating levels of testosterone.
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 luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels have been observed even at low doses as a consequence of feedback at the pituitary level.
Exemestane 25 mg daily had no significant effect on thyroid function [free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH)].
Pharmacokinetics
12.3 Pharmacokinetics Following oral administration to healthy postmenopausal women, plasma concentrations of exemestane decline polyexponentially with a mean terminal half-life of about 24 hours. 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. 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, exemestane appeared to be absorbed more rapidly in women with breast cancer than in the healthy women, with a mean t max of 1.2 hours in the women with breast cancer and 2.9 hours in healthy women. Approximately 42% of radiolabeled exemestane was absorbed from the gastrointestinal tract. A high-fat breakfast increased AUC and C max of exemestane by 59% and 39%, respectively, compared to fasted state. Distribution Exemestane is distributed extensively into tissues. Exe