title: Pharmacokinetics of estradiol valerate 2mg + dienogest 2mg (climodien® 2/2) after single and repeated oral administration in healthy postmenopausal women.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics and tolerability of estradiol valerate 2.0mg plus dienogest 2.0mg (Climodien® 2/2).
  
  
  METHODS
  This was an open single-and multiple-dose study.
  
  
  METHODS
  16 healthy postmenopausal women.
  
  
  METHODS
  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 R(1) = 3.3) and free estrone (R(1) = 2.4) was higher than that predicted from single-dose data (R(theor) = 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 (R(1) and R(theor) = 1.5). The pharmacokinetics of dienogest were not time dependent, the observed accumulation (AUC(0-24h) 627 vs 483 μg/L · h) was as predicted from single-dose results (R(1) and R(theor) = 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.
authors: Jenapharm GmbH & Co. KG, Otto-Schott-Strasse 15, D-07745, Jena, Germany, Holger.Zimmermann@Jenapharm.de.
authors: H
authors: H
authors: Zimmerman
authors: J J
authors: JJ
authors: Thebault
authors: T
authors: T
authors: Duvauchelle
authors: A
authors: A
authors: Mignot
authors: A
authors: A
authors: Renoux
authors: V
authors: V
authors: Gualano