Clinical Dosage Determination of a New Aromatase Inhibitor, Anastrozole, in Postmenopausal Japanese Women with Advanced Breast Cancer

Objective: To determine the recommended clinical dosage in Japan of a new aromatase inhibitor, anastrozole.

Design and Setting: A randomised, nonblinded, dose-comparative clinical pharmacology study was performed in healthy postmenopausal Japanese women, followed by a multicentre, randomised, nonblinded, parallel-group early phase II study in postmenopausal Japanese patients with advanced breast cancer.

Patients and Participants: 24 women were enrolled in the clinical pharmacological study and 73 in the efficacy study, of whom 70 were available for analysis.

Methods: In the initial phase of the clinical pharmacology study, 12 women received a single oral dose of anastrozole 0.5 or 1mg. Then, a further 12 women received anastrozole 0.5 or 1 mg/day for 14 days to study the tolerability and the pharmacokinetic and pharmacodynamic profiles of the drug. In the efficacy study, the patients with advanced breast cancer received anastrozole 0.5 or 1 mg/day for 12 weeks or more and tumour response was determined at 4-week intervals during treatment.

Results: Plasma concentrations of anastrozole reached steady state by days 8 to 10 of administration. The mean trough concentrations at steady state for anastrozole 0.5 and 1 mg/day were 15.8 and 35.9 μg/L, respectively. Anastrozole at both 0.5 and 1 mg/day significantly reduced plasma estradiol concentrations in comparison with baseline values. Daily exposure to estradiol at day 14 (geometric mean plasma estradiol concentrations) was significantly lower in participants receiving anastrozole 1 mg/day than in those receiving 0.5 mg/day (4.05 vs 5.95 pmol/L, p = 0.016). In the efficacy study, objective response rates were 27.8% (10 of 36) and 38.2% (13 of 34) in the 0.5 and 1 mg/day treatment groups, respectively. Complete response was observed in two patients in the 1 mg/day treatment group compared with none in the 0.5 mg/day treatment group.

Conclusions: The superiority of the 1 mg/day dosage in the clinical pharmacology study was also demonstrated in the efficacy study. Therefore, we recommend that the clinical dosage of anastrozole in Japan should be 1mg once daily.