Pharmacokinetics of estradiol valerate 2mg+dienogest 2mg (Climodien (R) 2/2) after single and repeated oral administration in healthy postmenopausal women

Objective: To evaluate the pharmacokinetics and tolerability of estradiol v alerate 2.0mg plus dienogest 2.0mg (Climodien(R) 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 s ingle and multiple daily intake of Climodien(R) 2/2 for 12 weeks. Accumulat ion during multiple administration was calculated from the area under the p lasma concentration-time curve (AUC). Changes in plasma levels of ether hor mones 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, respectiv ely). This was thought to be due to high interindividual variability in est rogen parameters, or the degree of extrapolation required when calculating the half-life (t(1/2)). The observed accumulation of total estrone after mu ltiple-drug administration was as predicted from single-dose results (R-1 a nd R-theor = 1.5). The pharmacokinetics of dienogest were not time dependen t, the observed accumulation (AUC(0-24h) 627 vs 483 mu g/L.h) was as predic ted 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(R) 2/2 (breast tension in five parti cipants and irregular vaginal bleeding in four) reflected its hormonal cont ent, and laboratory screening tests revealed no tolerability concerns. Conclusions: Estradiol may accumulate in plasma during multiple-drug admini stration with Climodien(R) 2/2 more than predicted from single-dose results . However, dienogest kinetics after multiple-drug administration were as pr edicted from single-dose results. Climodien(R) 2/2 demonstrated antiandroge nic effects and was well tolerated.