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A randomized, multiple-dose parallel study to compare the pharmacokinetic parameters of synthetic conjugated estrogens, A, administered as oral tablet or vaginal cream

Bhamra, Rupinder K. PhD1; Margolis, Marya B. PharmD2; Liu, James H. MD3; Hendy, Christopher H. PhD4; Jenkins, Rand G. BS5; DiLiberti, Charles E. MS6

doi: 10.1097/gme.0b013e3181f7a2d6
Original Articles
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Objective: A randomized, parallel-design study was conducted to determine the pharmacokinetic profile of synthetic conjugated estrogens A (SCE-A) vaginal cream (0.625 mg SCE-A/g) when administered at intervals (1 g once daily for 7 d, then twice weekly) over a 27-day period as compared with the pharmacokinetic profile of 0.3 mg SCE-A tablets administered once daily orally for 27 days.

Methods: Blood samples were collected 48 hours before initial dosing for baseline levels and at multiple occasions during the study until 48 hours after final study dosing (day 29). Maximum plasma concentration, time to maximum plasma concentration (Tmax), and area under the curve from 0 to 24 hours were calculated at days 1, 7, and 27; in addition, area under the curve from 0 to 48 hours was calculated at days 7 and 27, and area under the curve weekly (AUCweekly) values were calculated for both groups. For purposes of comparison, ratios of AUCweekly values for vaginal cream and oral tablets were analyzed.

Results: Compared with an oral daily dose of 0.3 mg SCE-A, the steady-state systemic exposure from vaginal cream application was considerably less, with the cream-to-oral ratio being 0.45 for baseline-adjusted (BA) unconjugated estradiol, 0.30 for BA unconjugated estrone, and 0.04 for unconjugated equilin (AUCweekly). At steady-state, the systemic blood levels of BA unconjugated estrone, BA unconjugated estradiol and unconjugated equilin were significantly lower in women who received biweekly application of 1 gm vaginal cream compared to women who took an oral daily dose of 0.3 mg SCE-A tablet.

Conclusions: After intravaginal application of SCE-A vaginal cream, absorption of estrogens was lower compared with absorption after oral administration. At steady state, the systemic exposure of equilin, estradiol, and estrone was significantly lower after twice-weekly administration of 1 g SCE-A vaginal cream compared with that achieved with an oral daily dose of a 0.3 mg SCE-A tablet.

From 1Teva Branded Pharmaceuticals USA, Woodcliff Lake, NJ; 2Teva Branded Pharmaceutical Products R&D, Inc., Horsham, PA; 3Case Medical Center, MacDonald Women's Hospital, Cleveland, OH; 4Novum Pharmaceutical Research Services, Pittsburgh, PA; 5PPD, Richmond, VA; and 6Montclair Bioequivalence Services, LLC, Montclair, NJ.

Received May 10, 2010; revised and accepted August 11, 2010.

Funding/support: This study was funded by Duramed Research, which is now Teva Branded Pharmaceutical Products R&D, Inc.

Financial disclosure/conflicts of interest: Rupinder Bhamra is an employee of Teva Pharmaceuticals, USA. Marya Margolis is an employee of Teva Branded Pharmaceutical Products R&D, Inc. Charles DiLiberti is a former employee of Teva Pharmaceuticals, USA. James Liu has consulted with Teva Branded Pharmaceutical Products R&D, Inc. Christopher Hendy and Rand Jenkins have no relevant disclosures.

Address correspondence to: Marya B. Margolis, PharmD, Teva Branded Pharmaceutical Products R&D, Inc., 425 Privet Road, Horsham, PA 19044. E-mail: Marya.margolis@barrlabs.com

©2011The North American Menopause Society