Aromasin (exemestane)

Exemestane, an aromatase inhibitor, is an antineoplastic agent.

Exemestane is an irreversible, selective steroidal aromatase inhibitor structurally related to the natural substrate androstenedione. Unlike nonsteroidal (type II) aromatase inhibitors (e.g., aminoglutethimide, letrozole), steroidal inhibitors such as exemestane (type I aromatase inhibitors) act as false substrates and are converted by aromatase to reactive alkylating intermediates that bind covalently to the substrate binding site of the enzyme; this binding to the active site of aromatase is irreversible, resulting in its inactivation (i.e., ''suicide'' inhibition). As a result of these differences, there appears to be a lack of cross-resistance in susceptible cancers between type I and II inhibitors.

Exemestane selectively inhibits the conversion of androgens to estrogens. Because estrogen acts as a growth factor for hormone-dependent breast cancer cells, reduction of serum and tumor concentrations of estrogen inhibits tumor growth and delays disease progression. In postmenopausal women, ovarian secretion of estrogen declines and conversion of adrenal androgens (mainly androstenedione and testosterone) to estrone and estradiol in peripheral tissues (adipose, muscle, and liver), catalyzed by the aromatase enzyme, is the principal source of estrogens.

Exemestane selectively inhibits the synthesis of estrogens and does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone. In dose-ranging (0.5-800 mg) studies, 25 mg was the minimum dose to exhibit maximum suppression of plasma estrogens. A single 25-mg exemestane dose reduces plasma estrogen (estradiol, estrone, and estrone sulfate) concentrations in postmenopausal women by as much as 85-95% within 2-3 days, with maximal suppression persisting up to at least 4-5 days after dosing.

After 4-12 weeks of exemestane therapy (25 mg daily) in postmenopausal women, plasma estrogen concentrations were suppressed by an average of 91-95%, and whole body aromatization was suppressed by 98%. Although an apparently lower suppression (e.g., by 60-70%) of plasma estrogens has been reported in some studies, these studies used a less-specific assay method (i.e., RIA) than the method (i.e., HPLC) used in studies reporting higher levels of suppression.

A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with exemestane dosages of 2.5 mg or more daily. Slight, dose-independent increases in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations have been observed even at low dosages as a result of negative feedback on the pituitary gland. At dosages up to 25 mg daily, no clinically important effect on circulating concentrations of androstenedione, dehydroepiandrostenedione sulfate, or 17-hydroxyprogesterone and only small decreases in circulating concentrations of testosterone are observed; however, at dosages of 200 mg or more daily, testosterone and androstenedione concentrations are increased.

17-Hydroexemestane, a metabolite, exhibits substantial intrinsic androgenic activity, which may become clinically important at high (e.g., 200 mg daily) exemestane dosages.

Exemestane is rapidly absorbed following oral administration, with peak concentrations in women with breast cancer or healthy women attained within about 1.2 or 2.9 hours, respectively. Approximately 42% of an oral dose of exemestane is absorbed from the gastrointestinal tract. Following repeated doses, the mean AUC in women with breast cancer is approximately twice that in healthy women.

Administration with a high-fat meal increases the AUC and peak plasma concentration of exemestane by 59 and 39%, respectively. Exemestane is approximately 90% protein bound (mainly to alpha1-acid glycoprotein and albumin). Exemestane is extensively metabolized via CYP3A4 and aldoketoreductases; metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug.

One metabolite, 17-hydroexemestane, may have androgenic activity. Exemestane is excreted similarly (42%) in both urine and feces; <1% isexcreted as unchanged drug in urine. The half-life of exemestane is approximately 24 hours.

USES: This medication is used to treat certain types of breast cancer (such as hormone-receptor-positive breast cancer) in women after menopause. Exemestane is also used to help prevent the cancer from returning. Some breast cancers are made to grow faster by a natural hormone called estrogen.

Exemestane decreases the amount of estrogen the body makes and helps to slow or reverse the growth of these breast cancers. Exemestane is usually not used in women of childbearing age.

Generic name: exemestane
Pronunciation: (ex-em-ESS-tain)

The following indications are listed for Aromasin:

• Advanced Breast Cancer Progress Post-Antiestrogen Therapy
• Hormone Receptor Positive Postmenopausal Early Breast Cancer After Adjuvant Tamoxifen

No ICD codes are available for this drug.