Anastrozole, in Postmenopausal Japanese Women
Anastrozole, in Postmenopausal Japanese Women
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 µµ/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.
Anastrozole is a new generation nonsteroidal aromatase inhibitor, which selectively and potently blocks the enzymatic synthesis of estrogen from androgen. Plasma estradiol concentrations in postmenopausal women are significantly reduced following anastrozole treatment. Anastrozole was demonstrated to possess great clinical usefulness in postmenopausal patients with breast cancer and has been approved as a new therapeutic drug for breast cancer in Europe and the USA.
In Japan, an earlier phase I clinical study in postmenopausal women with breast cancer was conducted to examine the safety, pharmacokinetics, pharmacodynamics and clinical efficacy of anastrozole at 1, 5 and 10mg daily doses. During treatment, one of the six patients receiving 1 mg/day reported very mild dizziness, headache and nausea. All of these adverse events were transient and resolved during the treatment. As there were no further adverse events reported in other treatment groups, anastrozole was considered to be well tolerated. The antitumour effects of anastrozole were comparable among the treatment groups: the proportion of objective responses [complete response (CR) and partial response (PR)] was 33.3 (2of6), 33.3 (2 of 6) and 25.0% (2 of 8) at the 1, 5 and 10 mg/day dosages, respectively. The fall in plasma estradiol concentrations at 24 hours after the administration of anastrozole was also not significantly different between the treatment groups. The clinical efficacy of anastrozole was therefore considered to be comparable among the three dosages.
The results of a clinical study in healthy postmenopausal women carried out overseas, however, suggested that the minimal dosage of anastrozole required to produce a maximal decrease in estradiol concentrations was 1mg. Additionally, a phase III dose-comparative study in postmenopausal patients with breast cancer showed no difference in the efficacy and tolerability of anastrozole 1 and 10 mg/day. Consequently, the recommended clinical dosage of 1 mg/day received regulatory approval for the treatment of advanced postmenopausal breast cancer in the USA and European countries.
Recently, we conducted a clinical pharmacological study in healthy postmenopausal women and an early phase II clinical study in patients with advanced breast cancer. In these studies, the safety, pharmacokinetics, pharmacodynamics and clinical efficacy of anastrozole 0.5 and 1 mg/day were compared. The most important purpose of these studies was to determine the clinically recommended dosage for Japanese patients.
These two studies were conducted in compliance with the 'Rule for Good Clinical Practice (GCP)' and in accordance with the 'Guidelines for Clinical Evaluation Methods of Antimalignant Tumor Drugs' and 'General Rules for Clinical and Pathological Recording of 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 µµ/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.
Anastrozole is a new generation nonsteroidal aromatase inhibitor, which selectively and potently blocks the enzymatic synthesis of estrogen from androgen. Plasma estradiol concentrations in postmenopausal women are significantly reduced following anastrozole treatment. Anastrozole was demonstrated to possess great clinical usefulness in postmenopausal patients with breast cancer and has been approved as a new therapeutic drug for breast cancer in Europe and the USA.
In Japan, an earlier phase I clinical study in postmenopausal women with breast cancer was conducted to examine the safety, pharmacokinetics, pharmacodynamics and clinical efficacy of anastrozole at 1, 5 and 10mg daily doses. During treatment, one of the six patients receiving 1 mg/day reported very mild dizziness, headache and nausea. All of these adverse events were transient and resolved during the treatment. As there were no further adverse events reported in other treatment groups, anastrozole was considered to be well tolerated. The antitumour effects of anastrozole were comparable among the treatment groups: the proportion of objective responses [complete response (CR) and partial response (PR)] was 33.3 (2of6), 33.3 (2 of 6) and 25.0% (2 of 8) at the 1, 5 and 10 mg/day dosages, respectively. The fall in plasma estradiol concentrations at 24 hours after the administration of anastrozole was also not significantly different between the treatment groups. The clinical efficacy of anastrozole was therefore considered to be comparable among the three dosages.
The results of a clinical study in healthy postmenopausal women carried out overseas, however, suggested that the minimal dosage of anastrozole required to produce a maximal decrease in estradiol concentrations was 1mg. Additionally, a phase III dose-comparative study in postmenopausal patients with breast cancer showed no difference in the efficacy and tolerability of anastrozole 1 and 10 mg/day. Consequently, the recommended clinical dosage of 1 mg/day received regulatory approval for the treatment of advanced postmenopausal breast cancer in the USA and European countries.
Recently, we conducted a clinical pharmacological study in healthy postmenopausal women and an early phase II clinical study in patients with advanced breast cancer. In these studies, the safety, pharmacokinetics, pharmacodynamics and clinical efficacy of anastrozole 0.5 and 1 mg/day were compared. The most important purpose of these studies was to determine the clinically recommended dosage for Japanese patients.
These two studies were conducted in compliance with the 'Rule for Good Clinical Practice (GCP)' and in accordance with the 'Guidelines for Clinical Evaluation Methods of Antimalignant Tumor Drugs' and 'General Rules for Clinical and Pathological Recording of Breast Cancer'.