Pharmacokinetics of orally administered estradiol valerate. Results of a single-dose cross-over bioequivalence study in postmenopausal women.
A randomized, single-dose cross-over study in 32 postmenopausal women was performed to demonstrate bioequivalence of two estradiol valerate containing formulations (first sequence of Klimonorm as test preparation). The serum levels of estradiol, free and conjugated estrone were measured until 48 h after an oral dosage of 4 mg estradiol valerate (CAS 979-32-8). The mean AUC(0-48) of estradiol was calculated as 1006.6 +/- 479.4 h x pg x ml-1 (Test) and 1015.2 +/- 555.2 h x pg x ml-1 (Reference). The corresponding (AUC(0-48) of the active metabolite, free estrone, exceeded that of estradiol at 3578.3 h x pg x ml-1 (Test) and 3485.1 h x pg x ml-1 (Reference). Much higher was the AUC(0-48) for conjugated estrone at 132.4 h x ng x ml-1 (Test) and 133.6 h x ng x ml-1 (Reference). Mean estradiol Cmax values of 39.8 +/- 17.7 pg/ml (Test) and 42.9 +/- 21.0 pg/ml (Reference) were attained 8.2 +/- 4.5 h (Test) and 10.0 +/- 5.9 h (Reference) after the administration of 4 mg estradiol valerate. Maximal free estrone concentrations of 163 pg/ml (Test) and 174.3 pg/ml (Reference) were reached after 7.2 h (Test) and 7.5 h (Reference). Maximal conjugated estrone concentrations of 15.5 ng/ml (Test) and 16.2 ng/ml (Reference) were reached after 2.4 h (Test) and 2.0 h (Reference). The terminal elimination half-life of estradiol was calculated at 16.9 +/- 6.0 h (Test) and 15.0 +/- 4.8 h (Reference), that of free estrone at 16.3 h (Test) and 13.5 h (Reference), that of conjugated estrone at 11.8 h (Test) and 10.6 h (Reference). After logarithmic transformation, the 90% confidence intervals of the AUC(0-48) and Cmax ratios for estradiol and also for the metabolites (free and conjugated estrone) were within the acceptance ranges for bioequivalence. Therefore the test preparation and the reference preparation are bioequivalent.
Zimmermann
H
H
Jenapharm GmbH & Co. KG, Department of Research and Development, Jena, Germany.
Koytchev
R
R
Mayer
O
O
Börner
A
A
Mellinger
U
U
Breitbarth
H
H
D000284:Administration, Oral; D019540:Area Under Curve; D018592:Cross-Over Studies; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004970:Estrone / Q000097:blood; D005260:Female; D006207:Half-Life; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause / Q000378:metabolism*; D011863:Radioimmunoassay; D015203:Reproducibility of Results; D013810:Therapeutic Equivalency
D004966:Estrogens, Conjugated (USP); D004970:Estrone; D004958:Estradiol