Eranfu Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Fulvestrant is a competitive estrogen receptor (ER) antagonist with an affinity comparable to estradiol. Fulvestrant blocks the trophic actions of estrogens without any partial agonist (estrogen-like) activity. The mechanism of action is associated with down-regulation of estrogen receptor protein levels.
Clinical trials in postmenopausal women with primary breast cancer have shown that Fulvestrant significantly down-regulates ER protein in ER positive tumors compared with placebo. There was also a significant decrease in progesterone receptor expression consistent with a lack of intrinsic estrogen agonist effects. It has also been shown that Fulvestrant 500 mg down-regulates ER and the proliferation marker Ki67, to a greater degree than Fulvestrant 250 mg in breast tumors in postmenopausal neo-adjuvant setting.
Pharmacokinetics: Absorption: After administration of Fulvestrant long-acting intramuscular injection, Fulvestrant is slowly absorbed and maximum plasma concentrations (C_max) 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 C_max 25.1 [35.3%] ng/mL, C_min 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 (Vd_ss) 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.
Biotransformation: 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-glucoronide metabolites) are either less active or exhibit similar activity to Fulvestrant in anti-estrogen 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 feces, 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 (t_1/2) 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 III studies, no difference in Fulvestrant's 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 trial conducted in subjects 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 subjects with hepatic impairment compared to healthy subjects. In patients administered Fulvestrant, an increase in exposure of this magnitude is expected to be well tolerated. Subjects with severe hepatic impairment (Child-Pugh class C) were not evaluated.
Pediatric population: The pharmacokinetics of Fulvestrant has been evaluated in a clinical trial conducted in 30 girls with Progressive Precocious Puberty associated with McCune Albright Syndrome. The pediatric patients were aged 1 to 8 years and received 4 mg/kg monthly intramuscular dose of Fulvestrant. The geometric mean (standard deviation) steady state trough concentration (C_min,_ss) and AUC_ss was 4.2 (0.9) ng/mL and 3680 (1020) ng*hr/mL, respectively. Although the data collected were limited, the steady-state trough concentrations of Fulvestrant in children appear to be consistent with those in adults.