952 Pharmacokinetics of repeated low-doses of exemestane (1, 2.5, 5, and 10 mg) in postmenopausal healthy volunteers

Abstract

Exemestane (EXE) is a new irreversible aromatase inhibitor being de-veloped for the treatment of hormone-sensitive breast cancer. The pharmacokinetics of EXE were investigated in 32 healthy postmenopausal volunteers treated for 7 days with doses of 1, 2.5, 5, and 10 mg/day (8 volunteers/dose). Plasma samples were collectedon day 5, 6, and 7 before the daily drug administration (Cmin) and on day 7 up to 24 h after drug intake. EXE plasma levels were determined by RIA (quantitation limit 12 pg/ml). On day 7, median EXE tmax was 1 h; Cmax averaged 0.83, 2.18, 7.29, and 11.04 ng/ml; AUC(0–24 h) averaged 2.30, 6.02, 15.24, and 29.98 ng.h/ml for the 1, 2.5, 5, and 10 mg doses, respectively. The analysis of Cmin values indicated that the EXE pharmacokinetics at day 7 were at steady-state for all doses. AUC(0– 24 h) and Cmax were compared by one-way analysis of variance after normalization to the 1 mg dose. Tmax were compared by Kruskal Wallis test. None of the parameters evaluated differed significantly. The correlations between AUC(0–24 h), Cmax and the EXE dose were statistically significant. In conclusion, the pharmacokinetics of EXE are dose-proportional at least up to the dose of 10 mg/day. Exemestane (EXE) is a new irreversible aromatase inhibitor being de-veloped for the treatment of hormone-sensitive breast cancer. The pharmacokinetics of EXE were investigated in 32 healthy postmenopausal volunteers treated for 7 days with doses of 1, 2.5, 5, and 10 mg/day (8 volunteers/dose). Plasma samples were collectedon day 5, 6, and 7 before the daily drug administration (Cmin) and on day 7 up to 24 h after drug intake. EXE plasma levels were determined by RIA (quantitation limit 12 pg/ml). On day 7, median EXE tmax was 1 h; Cmax averaged 0.83, 2.18, 7.29, and 11.04 ng/ml; AUC(0–24 h) averaged 2.30, 6.02, 15.24, and 29.98 ng.h/ml for the 1, 2.5, 5, and 10 mg doses, respectively. The analysis of Cmin values indicated that the EXE pharmacokinetics at day 7 were at steady-state for all doses. AUC(0– 24 h) and Cmax were compared by one-way analysis of variance after normalization to the 1 mg dose. Tmax were compared by Kruskal Wallis test. None of the parameters evaluated differed significantly. The correlations between AUC(0–24 h), Cmax and the EXE dose were statistically significant. In conclusion, the pharmacokinetics of EXE are dose-proportional at least up to the dose of 10 mg/day.