Pharmacokinetics of a single dose of fulvestrant prolonged-release intramuscular injection in postmenopausal women awaiting surgery for primary breast cancer.
OBJECTIVE
The aim of this study was to describe the pharmacokinetics of 3 different single doses of fulvestrant-a new estrogen receptor (ER) antagonist that downregulates the ER with no known agonist effects-administered as a prolonged-release IM formulation.


METHODS
Pharmacokinetic data were obtained in a randomized, partially blinded, placebo-controlled, parallel-group, Phase I/II multicenter trial involving postmenopausal women with primary breast cancer (clinical stages T1-T3, with tumors that were ER positive or of unknown ER status) awaiting curative-intent surgery. Patients received either IM fulvestrant (50, 125, or 250 mg), oral tamoxifen (20 mg, once daily), or oral placebo (once daily). Treatment started 2 to 3 weeks before surgery and blood was taken at various times up to 12 weeks after fulvestrant administration to assess pharmacokinetic variables.


RESULTS
A total of 200 patients entered the trial, of whom 58 took part in the pharmacokinetic analysis (50 mg, n = 20; 125 mg, n = 16; 250 mg, n = 22). Following single IM injections of fulvestrant, the median time to maximum concentration was 6.98, 6.98, and 6.96 days in the 50-, 125,- and 250-mg dose groups, respectively, with an overall range of 2 to 19 days). The plasma concentration-time profiles were primarily controlled by the rate of absorption from the injection site; post-peak plasma concentrations declined over time and were measurable up to 84 days after administration of fulvestrant 125 and 250 mg. Plasma concentrations at 28 days were 2- to 5-fold lower than the maximum value. Plasma concentration data for the 250-mg dose were best described by a 2-compartment pharmacokinetic model, with an apparent terminal phase half-life of approximately 49 days, beginning approximately 3 weeks after administration. Mean area under the plasma concentration-time curve for days 0 through 28 (AUC 0-28) was proportional for fulvestrant 50, 125, and 250 mg. For a doubling of the dose, an analysis of covariance model of the pharmacokinetic data projected an estimated increase in AUC 0-28 of a factor of 1.84 (95% CI, 1.67 to 2.04).


CONCLUSIONS
The IM formulation of fulvestrant used in this study had predictable, dose-linear pharmacokinetics. The prolonged-release properties of this formulation suggested that it may be well suited for the once-monthly dosing schedule intended for clinical use.
Robertson
John F R
JF
Nottingham City Hospital, Nottingham, United Kingdom. john.robertson@nottingham.ac.uk
Odling-Smee
William
W
Holcombe
Chris
C
Kohlhardt
Stanley R
SR
Harrison
Mike P
MP
D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000601:surgery; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D000077267:Fulvestrant; D006207:Half-Life; D006801:Humans; D007273:Injections, Intramuscular; D017698:Postmenopause; D013629:Tamoxifen / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
D018931:Antineoplastic Agents, Hormonal; D003692:Delayed-Action Preparations; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol