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


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.


Estradiol Estrone Dienogest Estradiol Valerate Bioequivalence Range 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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


  1. 1.
    Stanczyk F. Introduction: structure-function relationships, metabolism, pharmacokinetics and potency of progestins. Drugs Today 1996; 32Suppl. H: 1–14Google Scholar
  2. 2.
    Gräser T, Oettel M. Organ targeting with the oral progestin dienogest. Drugs Today 1996; 32Suppl. H: 43–55Google Scholar
  3. 3.
    Oettel M, Bervoas-Martin S, Elger W, et al. A 19-norprogestin without a 17α-ethinyl group 1: dienogest from a pharmacokinetic point of view. Drugs Today 1995; 31(7): 499–516Google Scholar
  4. 4.
    Gambrell Jr RD. The menopause: benefits and risks of estrogen-progestogen replacement therapy. Fertil Steril 1982; 37: 457–4PubMedGoogle Scholar
  5. 5.
    Nachtigall LE, Nachtigall RH, Nachtigall RD, et al. Estrogen replacement therapy: a 10-year prospective study in relationship to osteoporosis. Obstet Gynecol 1979; 53: 277–81PubMedGoogle Scholar
  6. 6.
    FDA HRT Working Group. Guidance for clinical evaluation of combined estrogen/progestin-containing drug products used for hormone replacement therapy of postmenopausal women. Menopause 1995; 2: 131–6Google Scholar
  7. 7.
    Christiansen C, Riis BJ. Five years with continuous combined oestrogen/progestogen therapy. Effects on calcium metabolism, lipoproteins, and bleeding pattern. Br J Obstet Gynaecol 1990; 97: 1087–92PubMedCrossRefGoogle Scholar
  8. 8.
    Luciano AA, Turksoy RN, Carleo J, et al. Clinical and metabolic responses of menopausal women to sequential versus continuous estrogen progestin replacement therapy. Obstet Gynecol 1988; 71:3–43Google Scholar
  9. 9.
    Hirvonen F, Malkonen M, Manninen V. Effects of different progestogens on lipoproteins during post-menopausal replacement therapy. N Engl J Med 1981; 304: 560–3PubMedCrossRefGoogle Scholar
  10. 10.
    Farish E, Fletcher CD, Hart DM, et al. A long-term study of the effects of norethisterone on lipoprotein metabolism in menopausal women. Clin Chim Acta 1983; 132: 193–8PubMedCrossRefGoogle Scholar
  11. 11.
    Anderson ABM, Sklovsky E, Sayers L, et al. Comparison of serum oestrogen concentrations in postmenopausal women taking estrone sulphate and estradiol Br Med J 1978; 1: 140–2Google Scholar
  12. 12.
    Gibaldi M, Perrier D. Pharmacokinetics (2nd ed, revised and expanded). Drugs and the pharmaceutical sciences. Vol. 15. New York: Dekker, 1982Google Scholar
  13. 13.
    Rowland M, Tozer T. Clinical pharmacokinetics-concepts and applications (2nd ed). Philadelphia: Lea & Feibiger, 1989Google Scholar
  14. 14.
    Steinijans VW, Hauschke D. International harmonization of regulatory bioequivalence requirements. Clin Res Reg Aff 1993; 10(4): 203–20CrossRefGoogle Scholar
  15. 15.
    Lobo RA, Cassidenti DL. Pharmacokinetics of oral 17β-estradiol. J Reprod Med 1992; 37(1): 77–84PubMedGoogle Scholar
  16. 16.
    Svensson LO, Johnson SH, Olsson SE. Plasma concentration of medroxyprogesteroner acetate, estradiol and estrone following oral administration of Klimaxil®, Trisequence®/ Provera® and Divina®. A randomized, single-blind, triple cross-over bioavailability study in menopausal women. Maturitas 1994; 18: 229–38PubMedCrossRefGoogle Scholar
  17. 17.
    Englund DE, Johansson EDB. Pharmacokinetic and pharmaco-dynamic studies on estradiol valerate administered orally to postmenopausal women. Acta Obstet Gynecol Scand Suppl 1997; 65: 27–31Google Scholar
  18. 18.
    Timmer CJ, Geurts TBP. Bioequivalence assessment of three different estradiol formulations in postmenopausal women in an open, randomized, single dose, 3 way cross-over study. Eur J Drug Metab Pharmacokinet 1999; 24: 47–53PubMedCrossRefGoogle Scholar
  19. 19.
    Düsterberg B, Schmidt-Gollwitzer M, Hümpel M. Pharmacokinetics and biotransformation of estradiol valerate in ovarectomized women. Horm Res 1985; 21: 145–54PubMedCrossRefGoogle Scholar
  20. 20.
    Scott RT, Ross B, Anderson C, et al. Pharmacokinetics of percutaneous estradiol: a crossover study using a gel and a transdermal system in comparison with oral micronized estradiol. Obstet Gynecol 1991; 77: 758–64PubMedGoogle Scholar
  21. 21.
    Schubert W, Cullberg G, Hedner T. Pharmacokinetic evaluation of oral 17β-estradiol and two different fat soluble analogues in ovariectomized women. Eur J Clin Pharmacol 1993; 44: 563–8PubMedCrossRefGoogle Scholar
  22. 22.
    Price TM, Blauer KL, Hansen M, et al. Single dose pharmacokinetics of sublingual versus oral administration of micronized 17β-estradiol. Obstet Gynecol 1997; 89: 340–5PubMedCrossRefGoogle Scholar
  23. 23.
    Zimmermann H, Koytchev R, Mayer O, et al. Pharmacokinetics of orally administered estradiol valerate. Results of a single dose cross-over bioequivalence study in postmenopausal women. Arzneimittelforschung 1998; 48: 941–7PubMedGoogle Scholar
  24. 24.
    Setnikar I, Rovati LC, Vens-Cappell B, et al. Pharmacokinetics of estradiol and of estrone during repeated transdermal or oral administration of estradiol. Arzneimittelforschung 1996; 46: 766–73PubMedGoogle Scholar
  25. 25.
    Sahlin L, von Schoultz B. Liver inclusive protein, lipid and carbohydrate metabolism. In: Oettel M, Schillinger E, editors. Handbook of experimental pharmacology 135/II: estrogens and antiestrogens II. Berlin: Springer-Verlag, 1999: 323–51Google Scholar

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

Personalised recommendations