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 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 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.
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 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 AUC0-∞ of exemestane
were decreased by 41% and 54%, respectively (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
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)].
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.
