Sign Out
Pharmacology: Many breast cancers have estrogen receptors, 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 estrogen receptor protein in human breast cancer cells.
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.
Pharmacodynamics: In a clinical study in postmenopausal women with primary breast cancer treated with single doses of fulvestrant 15-22 days prior to surgery, there was evidence of increasing downregulation of estrogen receptor 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 estrogen receptor pathway were also associated with a decrease in Ki67 labeling index, a marker of cell proliferation.
Pharmacokinetics: Absorption: After administration of fulvestrant long-acting intramuscular injection, fulvestrant is slowly absorbed and maximum plasma concentrations (Cmax) are reached after about 5 days. Administration of fulvestrant 500 mg regimen achieves exposure levels at, or close to, steady state within the first month of dosing (mean [CV]: AUC 475 [33.4%] ng·days/ml, Cmax 25.1 [35.3%] ng/ml, Cmin 16.3 [25.9%] ng/ml, respectively). At steady state, fulvestrant plasma concentrations are maintained within a relatively narrow range with up to an approximately 3-fold difference between maximum and trough concentrations. After intramuscular administration, the exposure is approximately dose proportional in the dose range 50 to 500 mg.
Distribution: Fulvestrant is subject to extensive and rapid distribution. The large apparent volume of distribution at steady state (Vdss) of approximately 3 to 5 l/kg suggests that distribution is largely extravascular. Fulvestrant is highly (99%) bound to plasma proteins. Very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) fractions are the major binding components. No interaction studies were conducted on competitive protein binding. The role of sex hormone-binding globulin (SHBG) has not been determined.
Metabolism: The metabolism of fulvestrant has not been fully evaluated, but involves combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids. Identified metabolites (includes 17-ketone, sulphone, 3-sulphate, 3- and 17-glucuronide metabolites) are either less active or exhibit similar activity to fulvestrant in anti-oestrogen models. Studies using human liver preparations and recombinant human enzymes indicate that CYP3A4 is the only P450 isoenzyme involved in the oxidation of fulvestrant, however, non-P450 routes appear to be more predominant in vivo. In vitro data suggest that fulvestrant does not inhibit CYP450 isoenzymes.
Elimination: Fulvestrant is eliminated mainly in metabolised form. The major route of excretion is via the faeces, with less than 1% being excreted in the urine. Fulvestrant has a high clearance, 11±1.7 ml/min/kg, suggesting a high hepatic extraction ratio. The terminal half-life (t½) after intramuscular administration is governed by the absorption rate and was estimated to be 50 days.
Special populations: In a population pharmacokinetic analysis of data from phase 3 studies, no difference in fulvestrant pharmacokinetic profile was detected with regard to age (range 33 to 89 years), weight (40-127 kg) or race.
Renal impairment: Mild to moderate impairment of renal function did not influence the pharmacokinetics of fulvestrant to any clinically relevant extent.
Hepatic impairment: The pharmacokinetics of fulvestrant has been evaluated in a single-dose clinical study conducted in women with mild to moderate hepatic impairment (Child-Pugh class A and B). A high dose of a shorter duration intramuscular injection formulation was used. There was up to about 2.5-fold increase in AUC in women with hepatic impairment compared to healthy women. In patients administered fulvestrant, an increase in exposure of this magnitude is expected to be well tolerated. Women with severe hepatic impairment (Child-Pugh class C) were not evaluated.
