Pharmacology of Exemestane

One-third of all breast cancers and two-thirds of all breast cancers in postmenopausal women are oestrogen-dependent. Anti-oestrogen strategies are therefore effective for the management of hormone-dependent breast cancer. Two strategies have been deployed to reduce the growth stimulatory effects of oestrogen:

• interfering with the ability of oestrogen to bind to its receptor
• decreasing circulating levels of oestrogen.

The basis for anti-oestrogen therapy is competitive occupation of the oestrogen receptors to reduce the number available for binding of endogenous oestrogen. This approach has been effective as an anticancer strategy, although there are no 'pure' anti-oestrogens currently available, since tamoxifen exhibits both oestrogen agonist and antagonist effects depending on the tissue type and hormonal environment.

Oestrogen deprivation offers another mechanism by which hormone-dependent tumour growth may be inhibited. Elucidation of the oestrogen biosynthesis pathway has identified a potential target involving the conversion of androgens to oestrogens by the aromatase enzyme. Aromatisation is the last step in oestrogen biosynthesis and antiaromatase agents have been developed to stop the conversion of androgens to oestrogen.

Competitive aromatase inhibitors are molecules that compete with the substrate androstenedione for non-covalent reversible binding to the active site of the enzyme to decrease the amount of oestrogen formed. Irreversible aromatase inhibitors are steroidal agents that inactivate aromatase. Both irreversible steroidal aromatase inactivators and reversible non-steroidal aromatase inhibitors have been developed for use in the clinical situation.

Aminoglutethimide was the prototype reversible aromatase inhibitor and, although effective at decreasing aromatisation, this agent inhibited a number of other CYP-450 enzymes, resulting in significant toxicity. Newer agents are now more effective and more specific.

Greater specificity has also been obtained with the irreversible steroidal antiaromatase agents. This class of compounds is structurally related to androstenedione. It is initially recognised by the aromatase enzyme as a false substrate and then transformed to an intermediate that binds irreversibly to the enzyme causing its inactivation. This type of interaction has the potential for enhanced selectivity and these inactivators cause potent and sustained inhibitory action for example, formestane, the prototype of this class of drugs, is 30- to 60- fold more potent than aminoglutethimide.

About Exemestance

Exemestane is a novel oral irreversible aromatase inactivator. It is rapidly absorbed and reaches peak plasma concentrations within 2 hours following oral administration of a 25 mg dose. Exemestane has a mean terminal half-life of 24 hours, which is shorter than for the non-steroidal inhibitors. The drug is eliminated by the liver and kidneys.

The potency and duration of aromatase inhibition in healthy postmenopausal volunteers exceeded initial expectations. A single oral dose of exemestane 25 mg caused a long-lasting reduction in plasma and urinary oestrogen levels, with maximal suppression occurring 2 to 3 days after dosing and persisting for 4 to 5 days.

Maximal inhibition of peripheral aromatase activity of 98% and inactivation of oestrogen production of 85% to 95% is observed with an oral dosage of 25 mg given once daily (Table 1). Oestrogen suppression is comparable to that of third-generation aromatase inhibitors. The selectivity of exemestane is confirmed by its lack of other endocrine effects. In comparison with other antiaromatase agents, there is extended aromatase inhibition with exemestane.

Exemestane has an excellent safety profile, with no significant drug toxicity at doses up to 600 mg/day. It is exceptionally well tolerated the maximum tolerated dose and dose limiting toxicity have not yet been identified. Adverse effects are usually mild to moderate, and include infrequent transient gastrointestinal effects, hot flushes, nausea, and fatigue.

Table 1 .Inhibition of aromatase activity by antiaromatase agents in
postmenopausal women with breast cancer.