Pharmacokinetic profile of intramuscular fulvestrant in advanced breast cancer

Clin Pharmacokinet. 2004;43(8):529-38. doi: 10.2165/00003088-200443080-00003.


Objective: To characterise the pharmacokinetics of a long-acting formulation of fulvestrant following intramuscular administration of single and multiple doses.

Study design: Pharmacokinetic investigations of single and multiple doses of fulvestrant were conducted within two global phase III efficacy studies that compared intramuscular fulvestrant with oral anastrozole in postmenopausal women with hormone-sensitive advanced breast cancer (study 0020, conducted in Europe, Australia and South Africa, and study 0021, conducted in North America).

Methods: Patients received once-monthly intramuscular injections of fulvestrant 250 mg (1 x 5 mL for < or =21 months in study 0020; 2 x 2.5 mL for < or =30 months in study 0021). Serial blood samples were collected for the first 28 days after the initial dose and immediately prior to all subsequent monthly doses. Plasma fulvestrant concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry.

Patients: Twenty-six (study 0020) and 193 (study 0021) postmenopausal women, comprising the pharmacokinetic subgroups of the phase III efficacy trials, were studied. Patients had shown disease progression or recurrence following previous hormonal therapy for advanced disease or had relapsed after adjuvant endocrine therapy with a nonsteroidal antiestrogen.

Outcome measures and results: For single-dose fulvestrant 250 mg, area under the concentration-time curve from time zero to 28 days (AUC(28)), maximum observed plasma concentration (C(max)), minimum observed plasma concentration at 28 days (C(min)) and time to maximum plasma concentration (t(max)) were determined. For multiple-dose fulvestrant 250 mg once monthly, steady-state trough concentrations (C(trough)) were determined. Plasma fulvestrant concentrations reached a peak at a median of 7 days (range 2-8 days) postdose, and declined biexponentially with a slower phase commencing approximately 2-3 weeks postdose. Intersubject variability in C(max) and AUC(28) was approximately 6-fold and 4-fold, respectively. Mean parameters for single-dose fulvestrant were: AUC(28), 148 microg. day/L; C(max), 8.2 microg/L; C(min), 2.6 microg/L; t(max), 7.0 days. Geometric mean C(trough) increased from 2.57 to 6.15 microg/L (study 0020) and from 2.38 to 6.52 microg/L (study 0021) over the first 6 months, reaching steady-state concentrations of approximately 6-7 microg/L (study 0020) or 9 microg/L (study 0021). Preliminary pharmacokinetic analysis, using a naive pooled data approach, suggests that observed single- and multiple-dose plasma profiles can be adequately described with a two-compartment kinetic model. Model-generated steady-state AUC(28) values were approximately 300 microg. day/L.

Conclusions: The intramuscular formulation of fulvestrant displays predictable kinetics and approximately 2-fold accumulation on administration once monthly. At the proposed therapeutic dosage (250 mg once monthly), plasma fulvestrant concentrations are maintained within a narrow range throughout the administration interval, thus ensuring stable systemic drug exposure during long-term treatment.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Hormonal / blood
  • Antineoplastic Agents, Hormonal / pharmacokinetics*
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Area Under Curve
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / radiotherapy
  • Double-Blind Method
  • Estradiol / analogs & derivatives*
  • Estradiol / blood
  • Estradiol / pharmacokinetics*
  • Estradiol / therapeutic use
  • Estrogen Antagonists / blood
  • Estrogen Antagonists / pharmacokinetics*
  • Estrogen Antagonists / therapeutic use
  • Female
  • Fulvestrant
  • Half-Life
  • Humans
  • Metabolic Clearance Rate
  • Middle Aged
  • Postmenopause


  • Antineoplastic Agents, Hormonal
  • Estrogen Antagonists
  • Fulvestrant
  • Estradiol