Pharmacokinetic profile of the fulvestrant loading dose regimen in postmenopausal women with hormone receptor-positive advanced breast cancer

Purpose: Fulvestrant is at least as effective as anostrozole in the treatment of postmenopausal women with advanced breast cancer whose disease has previously progressed or recurred on antiestrogen therapy. Pharmacokinetic data have shown that, at the approved dose (250 mg/month), it takes approximately 3-6 months for fulvestrant to reach steady-state levels. Theoretically, a more rapid attainment of steady state might reduce the number of early progressions. A pharmacokinetic model simulating plasma concentrations expected to be achieved with a fulvestrant loading dose (LD) regimen suggested that steady state might be achieved earlier with the LD. The aim of this study was to characterize the pharmacokinetics of the fulvestrant LD regimen. This phormacokinetic substudy was conducted within a phase III trial, EFECT (Evaluation of Fulvestrant versus Exemestane Clinical Trial), comparing fulvestrant with exemestane in postmenopausal women with hormone-sensitive advanced breast cancer whose disease had progressed or recurred following nonsteroidal aromatase inhibitor treatment. Patients and Methods: Patients received fulvestrant intramuscularly using a LD regimen of 500 mg on day 0, 250 mg on days 14 and 28, and then 250 mg each month thereafter. Blood samples were collected throughout the first month and on day 28 of each subsequent month. Plasma fulvestrant concentrations were determined by high-performance liquid chromatography-mass spectrometry and phormacokinetic parameters were estimated with nonlinear mixed-effects modeling. Results: Thirty-seven patients receiving fulvestrant were enrolled into the pharmacokinetic substudy, and 269 fulvestrant plasma concentrations were recorded. Maximum fulvestrant concentration (19.7 ng/mL) was observed at an average of 12 days within the first month and maintained at 12-15 ng/mL throughout the remainder of the dosing period. Conclusion: Steady-state plasma levels were attained within the first month of treatment with fulvestrant LD, in line with the predictions of the pharmacokinetic model.