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 ofActivelle (1 mg estradiol (E2) + 0.5 mg norethisterone acetate (NETA)) and the combined phase of Novofem (1 mg E2 + 1 mg NETA) and between the NETA components of the combined phase of Novofem (1 mg E2 + 1 mg NETA) and Trisequens (2 mg E2 + 1 mg NETA).


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 E2, estrone (E1; pharmacologically active metabolite of E2) 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 E2 and E1 AUC0-t (Novofem)/AUC0-t (Activelle) ratios were 105% and 100%, respectively; and the Cmax ratios 100% and 105%, respectively. Identical median tmax was observed for E2 (6 h) and for E1 (5 h). The NET AUC0-t (Novofem)/AUC0-t (Trisequens) ratio was 95%, and the corresponding Cmax ratio 98%. The median tmax for Novofem was 0.75 h and for Trisequens 1.0 h.


CONCLUSIONS
Bioequivalence was demonstrated for E2, E1 and NET in accordance with the study objectives.
Zdravkovic
M
M
Department of Clinical Pharmacology, Novo Nordisk A/S, Bagsvaerd, Denmark.
Müller
M
M
Larsen
S
S
Degenkolb
J
J
Pabst
G
G
D000284:Administration, Oral; D000368:Aged; D019540:Area Under Curve; D004958:Estradiol / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009640:Norethindrone / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D000077563:Norethindrone Acetate; D045167:Progesterone Congeners / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency
D045167:Progesterone Congeners; D004958:Estradiol; D000077563:Norethindrone Acetate; D009640:Norethindrone