Mechanism of Action

Many breast cancers have estrogen receptors (ER), and the growth of these tumors can be stimulated by estrogen. Fulvestrant is an estrogen receptor antagonist that binds to the estrogen receptor in a competitive manner with affinity comparable to that of estradiol. Fulvestrant downregulates the ER protein in human breast cancer cells.

In a clinical study in postmenopausal women with primary breast cancer treated with single doses of FASLODEX 15-22 days prior to surgery, there was evidence of increasing down regulation of ER with increasing dose. This was associated with a dose-related decrease in the expression of the progesterone receptor, an estrogen-regulated protein. These effects on the ER pathway were also associated with a decrease in Ki67 labeling index, a marker of cell proliferation.

In vitro studies demonstrated that fulvestrant is a reversible inhibitor of the growth of tamoxifen-resistant, as well as estrogen-sensitive human breast cancer (MCF-7) cell lines. In in vivo tumor studies, fulvestrant delayed the establishment of tumors from xenografts of human breast cancer MCF-7 cells in nude mice. Fulvestrant inhibited the growth of established MCF-7 xenografts and of tamoxifen-resistant breast tumor xenografts. Fulvestrant resistant breast tumor xenografts may also be cross-resistant to tamoxifen.

Fulvestrant showed no agonist-type effects in in vivo uterotropic assays in immature or ovariectomized mice and rats. In in vivo studies in immature rats and ovariectomized monkeys, fulvestrant blocked the uterotrophic action of estradiol. In postmenopausal women, the absence of changes in plasma concentrations of FSH and LH in response to fulvestrant treatment (250 mg monthly) suggests no peripheral steroidal effects.

Pharmacokinetics

Following intravenous administration, fulvestrant is rapidly cleared at a rate approximating hepatic blood flow (about 10.5 mL plasma/min/Kg). After an intramuscular injection plasma concentrations are maximal at about 7 days and are maintained over a period of at least one month, with trough concentration about one-third of C_max. The apparent half-life was about 40 days. After administration of 250 mg of fulvestrant intramuscularly every month, plasma levels approach steady-state after 3 to 6 doses, with an average 2.5 fold increase in plasma AUC compared to single dose AUC and trough levels about equal to the single dose C_max (see Table 1).

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