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® ( 1 mg estradiol (E 2 ) + 0.5 mg norethisterone acetate (NETA)) and the combined phase of Novofem (1 mg E 2 + 1 mg NETA) and between the NETA components of the combined phase of Novofem trade; (1 mg E 2 + 1 mg NETA) and Trisequens® (2 mg E 2 + I mg NETA). Subjects, materials and methods: The study design was double-blind, randomized, three-way, balanced six-sequence cross-over. 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 postmenopausal or bilaterally oophorectomized women. Plasma concentration profiles of E 2 , estrone (E 1 ; pharmacologically active metabolite of E 2 ) and norethindrone (NET; NET was determined since NETA is very rapidly metabolized to NET) were measured over 72 h, and 36 h, respectively. For the two former substances a baseline correction was performed by subtracting the mean of two predose measurements from the concentrations measured after dosing. Results: One subject dropped out of the study, completing only one treatment sequence; therefore, the results are based on 23 subjects. The baseline-corrected E 2 and E 1 AUC 0-t (Novofem ) / AUC 0-t (Activelle®) ratios were 105% and 100%, respectively; and the C max ratios 100% and 105%, respectively. Identical median t max was observed for E 2 (6 h) and for E 1 (5 h). The NET AUC 0-t (Novofem ) /AUC 0-t (Trisequens®) ratio was 95%, and the corresponding C max ratio 98%. The median t max for Novofem was 0.75 h and for Trisequens® 1.0 h. Conclusion: Bioequivalence was demonstrated for E 2 , E 1 and NET in accordance with the study objectives.