Clinical Drug Investigation

, Volume 20, Issue 2, pp 123–134 | Cite as

Pharmacokinetics of Estradiol Valerate 2mg + Dienogest 2mg (Climodien® 2/2) after Single and Repeated Oral Administration in Healthy Postmenopausal Women

  • H. Zimmerman
  • J. J. Thebault
  • T. Duvauchelle
  • A. Mignot
  • A. Renoux
  • V. Gualano
Clinical Pharmacokinetics

Abstract

Objective: To evaluate the pharmacokinetics and tolerability of estradiol valerate 2.0mg plus dienogest 2.0mg (Climodien® 2/2).

Design and Setting: This was an open single-and multiple-dose study.

Study Participants: 16 healthy postmenopausal women.

Interventions: Pharmacokinetic parameters were determined in plasma after single and multiple daily intake of Climodien® 2/2 for 12 weeks. Accumulation during multiple administration was calculated from the area under the plasma concentration-time curve (AUC). Changes in plasma levels of other hormones and sex hormone-binding globulin (SHBG) were also measured.

Results: The observed accumulation of estradiol (accumulation ratio R1 = 3.3) and free estrone (R1 = 2.4) was higher than that predicted from single-dose data (Rtheor = 1.7 and 2.0 for estradiol and free estrone, respectively). This was thought to be due to high interindividual variability in estrogen parameters, or the degree of extrapolation required when calculating the half-life (t1/2). The observed accumulation of total estrone after multiple-drug administration was as predicted from single-dose results (R1 and Rtheor = 1.5). The pharmacokinetics of dienogest were not time dependent, the observed accumulation (AUC0–24h 627 vs 483 μg/L · h) was as predicted from single-dose results (R1 and Rtheor = 1.3). Reduced total plasma testosterone levels confirmed the antiandrogenic effect of dienogest.

The main adverse events with Climodien® 2/2 (breast tension in five participants and irregular vaginal bleeding in four) reflected its hormonal content, and laboratory screening tests revealed no tolerability concerns.

Conclusions: Estradiol may accumulate in plasma during multiple-drug administration with Climodien® 2/2 more than predicted from single-dose results. However, dienogest kinetics after multiple-drug administration were as predicted from single-dose results. Climodien® 2/2 demonstrated antiandrogenic effects and was well tolerated.

Keywords

Estradiol Estrone Dienogest Estradiol Valerate Bioequivalence Range 

Notes

Acknowledgements

This study was sponsored by Jenapharm GmbH & Co. KG, Jena, Germany, a subsidiary of Schering AG, Berlin, Germany.

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Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • H. Zimmerman
    • 1
  • J. J. Thebault
    • 2
  • T. Duvauchelle
    • 2
  • A. Mignot
    • 2
  • A. Renoux
    • 2
  • V. Gualano
    • 2
  1. 1.Jenapharm GmbH & Co. KGJenaGermany
  2. 2.ASTER-CEPHACParis and Saint BenoîtFrance

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