Serum concentrations of 17beta-estradiol and estrone after multiple-dose administration of percutaneous estradiol gel in symptomatic menopausal women.
In two multicenter phase III efficacy studies, blood samples were obtained to evaluate the serum concentrations of 17beta-estradiol (E2) and unconjugated estrone (E1) after administration of a percutaneous gel or transdermal patch containing estradiol. In postmenopausal women, normal laboratory E2 and E1 serum concentrations range from 10-30 pg/mL and 20-40 pg/mL, respectively. Study subjects were healthy postmenopausal women with moderate to severe hot flushes occurring at least seven times daily or 60 times per week. Study 1 was a randomized, double-blind, multicenter study of percutaneous E2 gel 1.25 or 2.5 g (0.75 and 1.5 mg E2, respectively) versus placebo gel. Study 2 was a double-blind (blinded to E2 gel dose), randomized, active-controlled, multicenter, 12-week phase 3 study of E2 gel 0.625, 1.25, or 2.5 g (0.375, 0.75, or 1.5 mg E2, respectively) versus a transdermal E2 patch delivering 0.05 mg E2 per day. Serum E2 and E1 concentrations were evaluated at baseline and at week 12 for study 1 and at baseline and weeks 4, 8, and 12 for study 2 using radioimmunoassay. Median serum concentrations of E2 after 1.25- and 2.5-g gel administration appeared to be dose-proportional throughout both studies. In study 1, the median serum concentrations of E2 at week 12 were 33.5 and 65.0 pg/mL for 1.25- and 2.5-g gel dose, respectively. The corresponding E1 values were 49.0 and 58.0 pg/mL. In study 2, both E2 and E1 concentrations were relatively stable at weeks 4, 8, and 12. E2 values at week 12 for 0.625-, 1.25-, and 2.5-g gel doses and E2 patch were 25.0, 32.0, 60.0, and 38.5 pg/mL, respectively. The corresponding E1 values were 39.0, 41.0, 62.5, and 40.0 pg/mL. Application of the 1.25-g gel dose and a transdermal patch delivering 50 microg per day of E2 resulted in comparable median E2 and E1 concentrations. However, the 0.625-g gel dose did not produce E2 levels in a range expected to be consistently therapeutic in most postmenopausal women.
Brennan
J J
JJ
Clinical Operations, Solvay Pharmaceuticals, Inc., Marietta, Georgia 30062, USA.
Lu
Z
Z
Whitman
M
M
Stafiniak
P
P
van der Hoop
R G
RG
D000287:Administration, Topical; D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D004958:Estradiol / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D004970:Estrone / Q000097:blood*; D005260:Female; D005782:Gels; D006801:Humans; D008593:Menopause / Q000378:metabolism*; D008875:Middle Aged; D011863:Radioimmunoassay
D005782:Gels; D004970:Estrone; D004958:Estradiol