Fulvestrant was subject to extensive and rapid distribution. The apparent volume of distribution at steady state was approximately 3 to 5 L/kg. This suggests that distribution is largely extravascular. Fulvestrant was highly (99%) bound to plasma proteins; VLDL, LDL and HDL lipoprotein fractions appear to be the major binding components. The role of sex hormone-binding globulin, if any, could not be determined.

Metabolism and Excretion:

Biotransformation and disposition of fulvestrant in humans have been determined following intramuscular and intravenous administration of ₁₄C-labeled fulvestrant. Metabolism of fulvestrant appears to involve combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids, including oxidation, aromatic hydroxylation, conjugation with glucuronic acid and/or sulphate at the 2, 3 and 17 positions of the steroid nucleus, and oxidation of the side chain sulphoxide. Identified metabolites are either less active or exhibit similar activity to fulvestrant in antiestrogen models. Studies using human liver preparations and recombinant human enzymes indicate that cytochrome P-450 3A4 (CYP 3A4) is the only P-450 isoenzyme involved in the oxidation of fulvestrant; however, the relative contribution of P-450 and non-P-450 routes in vivo is unknown.

Fulvestrant was rapidly cleared by the hepatobiliary route with excretion primarily via the feces (approximately 90%). Renal elimination was negligible (less than 1%).

Special Populations:

Geriatric:
In patients with breast cancer, there was no difference in fulvestrant pharmacokinetic profile related to age (range 33 to 89 years).

Gender:
Following administration of a single intravenous dose, there were no pharmacokinetic differences between men and women or between premenopausal and postmenopausal women. Similarly, there were no differences between men and postmenopausal women after intramuscular administration.

Race:
In the advanced breast cancer treatment trials, the potential for pharmacokinetic differences due to race have been evaluated in 294 women including 87.4% Caucasian, 7.8% Black, and 4.4% Hispanic. No differences in fulvestrant plasma pharmacokinetics were observed among these groups. In a separate trial, pharmacokinetic data from postmenopausal ethnic Japanese women were similar to those obtained in non-Japanese patients.

Renal Impairment:
Negligible amounts of fulvestrant are eliminated in urine; therefore, a study in patients with renal impairment was not conducted. In the advanced breast cancer trials, fulvestrant concentrations in women with estimated creatinine clearance as low as 30 mL/min were similar to women with normal creatinine.

Hepatic Impairment:
Fulvestrant is metabolized primarily in the liver. In clinical trials in patients with locally advanced or metastatic breast cancer, pharmacokinetic data were obtained following administration of a 250 mg dose of FASLODEX to 261 patients classified as having normal liver function and to 24 patients with mild impairment. Mild impairment was defined as an alanine aminotransferase concentration (at any visit) greater than the upper limit of the normal (ULN) reference range, but less than 2 times the ULN; or if any 2 of the following 3 parameters were between 1- and 2-times the ULN: aspartate aminotransferase, alkaline phosphatase, or total bilirubin.

There was no clear relationship between fulvestrant clearance and hepatic impairment and the safety profile in patients with mild hepatic impairment was similar to that seen in patients with no hepatic impairment. Safety and efficacy have not been evaluated in patients with moderate to severe hepatic impairment (see PRECAUTIONS-Hepatic Impairment and DOSAGE AND ADMINISTRATION-Hepatic Impairment sections).

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