Pharmacokinetic Profile of Intramuscular Fulvestrant in Advanced Breast Cancer

Patients received once-monthly intramuscular injections of fulvestrant 250mg (1 × 5mL for ≤21 months in study 0020; 2 × 2.5mL for ≤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.

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.

For single-dose fulvestrant 250mg, area under the concentration-time curve from time zero to 28 days (AUC₂₈), 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 250mg 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 AUC28 was approximately 6-fold and 4-fold, respectively. Mean parameters for single-dose fulvestrant were: AUC28, 148 μg · day/L; C_max, 8.2 μg/L; C_min, 2.6 μg/L; t_max, 7.0 days. Geometric mean C_trough increased from 2.57 to 6.15 μg/L (study 0020) and from 2.38 to 6.52 μg/L (study 0021) over the first 6 months, reaching steady-state concentrations of approximately 6–7 μg/L (study 0020) or 9 μg/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 AUC₂₈ values were approximately 300 μg · day/L.

The intramuscular formulation of fulvestrant displays predictable kinetics and approximately 2-fold accumulation on administration once monthly. At the proposed therapeutic dosage (250mg 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.