Riliz Mechanism of Action

Pharmacology: Pharmacodynamics: Dienogest is a nortestosterone derivative with no androgenic but rather an antiandrogenic activity of approximately one-third of that of cyproterone acetate. Dienogest binds to the progesterone receptor of the human uterus with only 10% of the relative affinity of progesterone. Despite its low affinity to the progesterone receptor, dienogest has a strong progestogenic effect in vivo. Dienogest has no significant androgenic, mineralocorticoid or glucocorticoid activity in vivo.
Dienogest acts on endometriosis by reducing the endogenous production of estradiol and thereby suppresses the trophic effects of estradiol on both the eutopic and ectopic endometrium. When given continuously, dienogest leads to a hypoestrogenic, hypergestagenic endocrine environment causing initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions.
Additional direct antiproliferative, immunologic and antiangiogenic effects seem to contribute to the inhibitory action of dienogest on cell proliferation.
Pharmacokinetics: Dienogest is rapidly and almost completely absorbed after oral administration. Peak serum concentrations of 47 ng/mL are reached within 1.5 hours after single administration. The bioavailability of dienogest is about 91%. Food does not affect the bioavailability of dienogest. The pharmacokinetics of dienogest is dose-proportional within the dose range of 1 to 8 mg.
The pharmacokinetics of dienogest are not influenced by sex hormone binding globulin (SHBG) levels. Following daily intake, drug serum levels increase about 1.24-fold reaching steady-state conditions after 4 days of treatment. The pharmacokinetics of dienogest after repeated administration can be predicted from single dose pharmacokinetics of the drug.
Dienogest is bound to serum albumin and does not bind to SHBG or corticoid binding globulin (CBG). About 10% of the total serum drug concentration is present as free steroid, 90% is non-specifically bound to albumin.
The apparent volume of distribution (Vd/F) of dienogest is 40 L.
Dienogest is completely metabolized by the known pathways of steroid metabolism, with the formation of endocrinologically mostly inactive metabolites. Based on in vitro and in vivo studies, CYP3A4 is the major enzyme involved in the metabolism of dienogest. The metabolites are excreted very quickly so that in plasma unchanged dienogest is the dominating fraction.
The metabolic clearance rate from serum (CL/F) is 64 mL/min.
Dienogest serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of approximately 9 to 10 hours. Dienogest is excreted in form of metabolites which are excreted at a urinary to fecal ratio of about 3:1 after oral administration of 0.1 mg/kg. The half-life of urinary metabolites excretion is 14 hours. Following oral administration, approximately 86% of the dose administered is eliminated within 6 days, the bulk of this amount excreted within the first 24 hours, mostly with the urine.
Dienogest has not been studied in patients with renal or hepatic impairment.