Pharmacokinetics of dienogest as a single drug or in combination with estradiol valerate or ethinylestradiol

This article reviews three different studies which were performed to compar e single and multiple dose pharmacokinetics of dienogest alone or in combin ation with estrogens, with 30 mu g ethinylestradiol in study 2, and in comb ination with 2 mg estradiol valerate in study 3. In study 1 dienogest was u sed alone in a dose of 1 mg and with an administration interval of 12 h. In studies 2 and 3 dienogest was dosed at 2 mg every 24 h. The clinical and l aboratory tolerability was good in all three studies. Maximum serum concent rations of dienogest were 23 and 32 ng/ml, 51 and 69 ng/ml, and 54 and 66 n g/ml after single and multiple dose in studies 1, 2 and 3, respectively, an d were generally reached after 1-3 h. Terminal half-lives were highest in p ostmenopausal women in study 3 at approximately 11 h, whereas in young wome n (studies 1 and 2) terminal half-lives were between 6 and 10 h. The cleara nce CI/F was about 4 I/h in young women in studies I and 2 after the single dose. It was unchanged after the multiple dose in study 1, but decreased t o about 3 I/h after the multiple dose in study 2. In postmenopausal women t he clearance (CI/F) was generally lower at 3 lih but it did not change afte r the multiple dose. Thus, it could be concluded that the pharmacokinetics of dienogest is linear and not time dependent when dienogest is administere d alone or in combination with estradiol valerate, whereas after combinatio n with ethinylestradiol it is not linear. Nonlinear behavior of progestins after multiple administration in combination with ethinylestradiol is a typ ical finding for all investigated nortestosterone-derived progestins, such as levonorgestrel, desogestrel or gestodene. Nevertheless, the influence of ethinylestradiol on dienogest metabolism was much lower than on levonorges trel or gestodene metabolism. (C) Prous Science. All rights reserved.