Oligest Mechanism of Action

Pharmacotherapeutic group: Progestogens. ATC code: G03DB08.
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.
Data on efficacy: Superiority of dienogest over placebo was demonstrated in a 3-months study including 102 patients with dienogest for the reduction of endometriosis-associated pelvic pain (EAPP). Endometriosis-associated pelvic pain was measured on a Visual Analog Scale (VAS) (0-100 mm). After 3 months of treatment with dienogest, a statistically significant difference compared to placebo (Δ=12.3 mm; 95% CI: 6.4-18.1; p<0.0001) and a clinically meaningful reduction of pain compared to baseline (mean reduction=27.4 mm±22.9) were demonstrated.
After 3 months of treatment, a reduction of endometriosis-associated pelvic pain by 50% or more without relevant increase of concomitant pain medication was achieved in 37.3% of patients on dienogest (placebo:19.8%); a reduction of endometriosis-associated pelvic pain by 75% or more without relevant increase of concomitant pain medication was achieved in 18.6% of patients on dienogest (placebo: 7.3%).
The open-label extension to this placebo-controlled study suggested a continued improvement of endometriosis-associated pelvic pain for a treatment duration of up to 15 months.
The placebo-controlled results were also supported by the results obtained in a 6 months active-controlled study versus a GnRH agonist including 252 patients with endometriosis. The studies have shown that patients who received a daily dose of 2 mg dienogest demonstrated a reduction of endometriotic lesions after 6 months of treatment.
Pharmacokinetics: Absorption: Orally administered dienogest is rapidly and almost completely absorbed. Peak serum concentrations of 47 ng/ml are reached at about 1.5 hours after single ingestion. Bioavailability is about 91%. The pharmacokinetics of dienogest are dose-proportional within the dose range of 1-8 mg.
Distribution: Dienogest is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). 10% of the total serum drug concentration is present as free steroid, 90% is non-specifically bound to albumin.
The apparent volume of distribution (V_d/F) of dienogest is 40 L.
Metabolism/Biotransformation: Dienogest is completely metabolized by the known pathways of steroid metabolism, with the formation of metabolites which are mostly inactive endocrinologically. 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; therefore in plasma, unchanged dienogest is the dominating fraction.
The metabolic clearance rate from serum (Cl/F) is 64 ml/min.
Elimination/Excretion: Dienogest serum levels decrease in 2 phases. The terminal disposition phase is characterized by a half-life of approximately 9 to 10 hours. Dienogest is excreted in the form of inactive 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 administered dose is eliminated within 6 days. Most of the drug is excreted in the urine within the first 24 hours.
Steady-state conditions: Pharmacokinetics of dienogest are not influenced by SHBG levels. Following daily ingestion drug serum levels increase about 1.24-fold reaching steady-state conditions after 4 days of treatment. The pharmacokinetics of dienogest after repeated administration of OLIGEST can be predicted from single dose pharmacokinetics.
Pharmacokinetics in Special Population: Dienogest has not been studied specifically in renally impaired subjects. Dienogest has not been studied in subjects with hepatic impairment.
Toxicology: Preclinical safety data: Preclinical data reveal no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.