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. 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
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).
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
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 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).
Studies using human liver preparations indicate that cytochrome P-450 3A4 (CYP
3A4) is the principal isoenzyme involved in the oxidation of exemestane.
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.
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).
The influence of race on exemestane pharmacokinetics has not been
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).
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 less than 35 mL/min/1.73 m2) compared
with the AUC in healthy volunteers (see PRECAUTIONS).
The pharmacokinetics of exemestane have not been studied in
Exemestane is metabolized by cytochrome P-450 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. In a pharmacokinetic interaction study of 10 healthy
postmenopausal volunteers pretreated with potent CYP 3A4 inducer rifampicin 600
mg daily for 14 days followed by a single dose of exemestane 25 mg, the mean
plasma Cmax and AUC 0–∞ of
exemestane were decreased by 41% and 54%, respectively (see PRECAUTIONS and DOSAGE AND
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)].
Coagulation and Lipid Effects
In study 027 of postmenopausal women with early breast cancer
treated with exemestane (N=73) or placebo (N=73), there was no change in the
coagulation parameters activated partial thromboplastin time [APTT], prothrombin
time [PT] and fibrinogen. Plasma HDL cholesterol was decreased 6–9% in
exemestane treated patients; total cholesterol, LDL cholesterol, triglycerides,
apolipoprotein-A1, apolipoprotein-B, and lipoprotein-a were unchanged. An 18%
increase in homocysteine levels was also observed in exemestane treated patients
compared with a 12% increase seen with placebo.