Dienosis Mechanism of Action

Pharmacotherapeutic group: Progestogens. ATC code: G03D.
Pharmacology: Pharmacodynamics: Mechanism of action: Dienogest acts on endometriosis by reducing the endogenous production of estradiol and thereby suppressing 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 properties, like immunologic and antiangiogenic effects, seem to contribute to the inhibitory action of dienogest on cell proliferation.
Pharmacodynamics effects: 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.
Clinical efficacy and safety: Data on efficacy: Superiority of Dienogest 2 mg tablets over placebo with regard to reduction of endometriosis-associated pelvic pain (EAPP) and clinically meaningful reduction of pain compared to baseline were demonstrated in a 3-month study including 102 patients on Dienogest 2 mg tablets. EAPP was measured on a Visual Analog Scale (VAS) (0-100 mm). After 3 months of treatment with Dienogest 2 mg tablets, a statistically significant difference compared to placebo (△=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, reduction of EAPP by 50% or more without relevant increase of concomitant pain medication was achieved in 37.3% of patients on Dienogest 2 mg tablets (placebo: 19.8%); a reduction of EAPP by 75% or more without relevant increase of concomitant pain medication was achieved in 18.6% of patients on Dienogest 2 mg tablets (placebo: 7.3%).
The open-label extension to this placebo-controlled study showed a continued improvement of endometriosis-associated pelvic pain for a treatment duration of up to 15 months (mean reduction at end of treatment = 43.2 ± 21.7 mm).
In addition, efficacy on endometriosis-associated pelvic pain was shown in a 6-month comparative trial of Dienogest 2 mg tablets versus the GnRH analogue leuprorelin acetate (LA) including 120 patients on Dienogest 2 mg tablets. EAPP was measured on a VAS (0-100 mm). A clinically meaningful reduction of pain compared to baseline was observed in both treatment groups (Dienogest 2 mg tablets: 47.5 ± 28.8 mm, LA: 46.0 ± 24.8 mm). Non-inferiority versus LA based on a pre-defined non-inferiority margin of 15 mm was demonstrated (p<0.0001).
Three studies including a total of 252 patients who received a daily dose of 2 mg dienogest demonstrated a substantial reduction of endometriotic lesions after 6 months of treatment.
A randomized, double-blind, parallel-group study (n=20 to 23 per dose group) investigated pharmacodynamics effects of four dienogest doses (0.5, 1.0, 2.0, or 3.0 mg/day) for a maximum of 72 days. Ovulations were observed in 14% and 4% of women of the 0.5 mg and 1 mg groups, respectively. No ovulation occurred in the 2 mg and 3 mg groups. In the 2 mg group, ovulation was confirmed in 80% of women within 5 weeks after cessation of therapy. Dienogest 2 mg tablets 2 mg tablets has not been tested for contraceptive efficacy in larger studies.
The efficacy of Dienogest 2 mg tablets 2 mg tablets was demonstrated in the treatment of endometriosis related symptoms (pelvic pain, dysmenorrhea, and dyspareunia) in a 12-month study with 111 female adolescents (after menarche between 12 and 18 years of age).
Data on safety: Endogenous estrogen levels are only moderately suppressed during treatment with Dienogest 2 mg tablets.
Bone mineral density (BMD) was assessed in 21 adult patients before and after 6 months of treatment and there was no reduction in mean BMD. In a 12-months study involving 111 female adolescents, 103 had BMD measurements. The mean relative change in BMD of the lumbar spine (L2-L4) from baseline was -1.2%. In a subset of the patients with decreased BMD a follow-up measurement was performed 6 months after end of treatment and showed an increase in BMD towards baseline levels.
No significant impact on standard laboratory parameters, including hematology, blood chemistry, liver enzymes, lipids, and HbA1C was observed during treatment with Dienogest 2 mg tablets 2 mg tablets for up to 15 months (n=168).
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 concentrations are present as free steroid, 90% are non-specifically bound to albumin. The apparent volume of distribution (Vd/F) of dienogest is 40 l.
Metabolism/Biotransformation: 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.
Elimination/Excretion: Dienogest serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of approximately 9-10 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 h, mostly with the urine.
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 Dienogest 2 mg tablets can be predicted from single dose pharmacokinetics.
Toxicology: Preclinical safety data: Preclinical data reveal no special risks for humans based on conventional studies of safety pharmacology, 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.