Bioequivalence and relative bioavailability of three estradiol and norethisterone acetate-containing hormone replacement therapy tablets

Objective: The primary objective was to demonstrate bioequivalence between the estrogen components of Activelle (R) (1 mg estradiol (E-2) + 0.5 mg nor ethisterone acetate (NETA)) and the combined phase of Novofem (TM) (1 mg E- 2 + 1 mg NETA) and between the NETA components of the combined phase of Nov ofem (TM) (1 mg E-2 + 1 mg NETA) and Trisequens (R) (2 mg E-2 + 1 mg NETA). Subjects, materials and methods: The study design was double-blind, random ized, three-way, balanced six-sequence crossover. The washout period was 14 days between treatments. Single doses of the above-described tablets were administered in the morning following an overnight fast to 24 healthy postm enopausal or bilaterally oophorectomized women. Plasma concentration profil es of E-2, estrone (E-1; pharmacologically active metabolite of E-2) and no rethindrone (NET; NET was determined since NETA is very rapidly metabolized to NET) were measured over 72 h, and 36 h, respectively. For the two forme r substances a baseline correction was performed by subtracting the mean of two predose measurements from the concentrations measured after dosing. Re sults: One subject dropped out of the study, completing only one treatment sequence; therefore, the results are based on 23 subjects. The baseline-cor rected E-2 and E-1 AUC(0-t) (Novofem (TM))/ AUC(0-t) (Activelle (R)) ratios were 105% and 100%, respectively; and the Cma., ratios 100% and 105%, resp ectively. Identical median tma, was observed for E-2 (6 h) and for E-1 (5 h ). The NET AUC(0-t) (Novofem (TM))/AUC(0-t) (Trisequens (R)) ratio was 95%, and the corresponding C-max ratio 98%. The median t(max) for Novofem (TM) was 0.75 h and for Trisequens (R) 1.0 h. Conclusion: Bioequivalence was dem onstrated for E-2, E-1 and NET in accordance with the study objectives.