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Population pharmacokinetic/pharmacodynamic evaluation of low-dose drospirenone with 17β-estradiol in postmenopausal women with moderate to severe vasomotor symptoms

Sutter, Gabriele PhD1; Schmelter, Thomas PhD1; Gude, Kerstin MD, PhD1; Schaefers, Matthias MD, PhD1; Gerlinger, Christoph PhD1,2; Archer, David F. MD3

doi: 10.1097/GME.0b013e31829c12e8
Original Articles

Objective This study aims to characterize the pharmacokinetics/pharmacodynamics of drospirenone and estradiol in the treatment of postmenopausal women with moderate to severe vasomotor symptoms and to explore the relationship between the serum exposures of estradiol and drospirenone and efficacy, measured by reductions in moderate to severe hot flushes.

Methods Participants in a 12-week, double-blind, randomized, placebo-controlled study of daily drospirenone/estradiol in two low-dose combinations (0.25 mg/0.5 mg and 0.5 mg/0.5 mg), estradiol (0.3 mg), or placebo provided infrequent serum samples for pharmacokinetic analysis of estradiol and drospirenone, with additional frequent sampling during 24 hours in a study subset.

Results Estradiol steady-state serum concentrations were described by a one-compartmental model with first-order elimination and zero-order absorption. The pharmacokinetics of drospirenone was described by a linear open two-compartment model with first-order elimination kinetics from the central compartment and delayed first-order absorption kinetics. A total of 1,516 serum estradiol concentrations and 736 serum drospirenone concentrations (n = 251) from 383 women were evaluated. Baseline estradiol concentrations increased with rising body mass index, and apparent clearance of estradiol at steady state was 39% higher in smokers versus nonsmokers. The serum exposures of both estradiol and drospirenone affected efficacy, as analyzed by a generalized linear model. Smoking had a negative effect on the efficacy of hormone therapy.

Conclusions The efficacy of low-dose drospirenone/estradiol for reducing vasomotor symptoms correlates with the serum exposure of estradiol and, for the first time, the serum exposure of drospirenone. Smoking adversely affects the clearance of estradiol and the efficacy of treatment.

From 1Bayer Pharma AG, Berlin, Germany; 2Gynecology, Obstetrics, and Reproductive Medicine, University Medical School of Saarland, Homburg/Saar, Germany; and 3Clinical Research Center, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA.

Received February 27, 2013; revised and accepted May 15, 2013.

The authors were not compensated and retained full editorial control over the content of this manuscript.

Funding/support: This study was supported by funding from Bayer Pharma AG (Berlin, Germany). Medical writing support for this manuscript was provided by Bill Wolvey of PAREXEL and funded by Bayer Pharma AG.

Financial disclosure/conflicts of interest: D.F.A. serves as a consultant to Abbott, Agile, Bayer, CHEMO, Depomed, Endoceutics, Ferring Pharmaceuticals, HRA Pharma, and Merck, and has previously served as a consultant to Schering-Plough, Organon, Shionogi, Teva, and Warner Chilcott. He has received grants from Abbott, Bayer Healthcare, Endoceutics, Pfizer, Teva, Warner Chilcott, and Watson Pharmaceuticals, and speaking honoraria from Bayer Healthcare, Besins, Ferring Pharmaceuticals, and Pfizer. Other authors are full-time employees of Bayer Pharma AG.

Address correspondence to: Thomas Schmelter, PhD, Global Clinical Statistics, Bayer Pharma AG, Sellerstr. 31, Berlin 13353, Germany. E-mail:

© 2014 by The North American Menopause Society.