Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties
Pharmacotherapeutic group: Sex hormones and modulators of the genital system, progestogens and oestrogens, fixed combinations.
ATC code: G03AA10


This oestrogen-progestogen combination acts by inhibiting ovulation by suppression of the mid- cycle surge of luteinising hormone, the inspissation of cervical mucus so as to constitute a barrier to sperm, and the rendering of the endometrium unreceptive to implantation.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
Gestodene

Orally administered gestodene is rapidly and completely absorbed. Following single ingestion of Gynera, maximum drug serum levels of 4ng/ml are reached at about 1.0 hour. Thereafter, gestodene serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of 12-15 hours. For gestodene, an apparent volume of distribution of 0.7 l/kg and a metabolic clearance rate from serum of about 0.8 ml/min/kg were determined. Gestodene is not excreted in unchanged form but as metabolites, which are eliminated with a half-life of about 1 day. Gestodene metabolites are excreted at a urinary to biliary ratio of about 6:4. The biotransformation follows the known pathways of steroid metabolism. No pharmacologically active metabolites are known.

Gestodene is bound to serum albumin and to SHBG (sex hormone binding globulin). Only 1-2% of the total serum drug levels are present as free steroid, about 50-70% are specifically bound to SHBG. The relative distribution (free, albumin-bound, SHBG-bound) depends on the SHBG concentrations in the serum. Following induction of the binding protein, the SHBG-bound fraction increases while the unbound and the albumin-bound fractions decrease.

Following daily repeated administration of Gynera, gestodene concentrations in the serum increase by a factor of 2.8. Mean serum levels are fourfold higher at steady-state conditions which are reached during the second half of a treatment cycle. The pharmacokinetics of gestodene is influenced by SHBG serum levels. Under treatment with Gynera, a threefold increase in the serum SHBG levels has been observed for the first treatment cycle. Due to the specific binding of gestodene to SHBG, the increase in SHBG levels is accompanied by an almost parallel increase in gestodene serum levels. After three treatment cycles the extent of SHBG induction per cycle does not change any more. The absolute bioavailability of gestodene was determined to be 99% of the dose administered.


Ethinylestradiol
Orally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of Gynera, maximum drug serum levels of 82 pg/ml are reached at 1.4 hours. Thereafter, ethinylestradiol serum levels decrease in two phases characterized by half-lives of 1-2 hours and about 20 hours. Because of analytical reasons, these parameters can only be calculated following the administration of higher doses. For ethinylestradiol, an apparent volume of distribution of about 5 l/kg and a metabolic clearance rate from serum of about 5ml/min/kg were determined.
Ethinylestradiol is highly but non-specifically bound to serum albumin. About 2% of drug levels are present unbound. During absorption and first liver passage, ethinylestradiol is metabolized resulting in a reduced absolute and variable oral bioavailability. Unchanged drug is not excreted.
Ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. with a half-life of about 1 day.

According to the half-life of the terminal disposition phase from serum and the daily ingestion, steady-state serum levels are reached after 3-4 days and are higher by 30-40% as compared to a single dose.

During established lactation, 0.02% of the daily maternal dose could be transferred to the newborn via milk.

The systemic availability of ethinylestradiol might be influenced in both directions by other drugs.
There is, however, no interaction with high doses of vitamin C. Ethinylestradiol induces the hepatic synthesis of SHBG and CBG (corticoid binding globulin) during continuous use. The extent of SHBG induction, however, depends on the chemical structure and the dose of the co-administered progestogen. During treatment with Gynera, SHBG concentrations in the serum increased from 69nmol/l to 198nmol/l in the first and to 210nmol/l in the third cycle. Serum concentrations of CBG were increased from 37μg/ml to 85μg/ml in the first cycle and remained constant thereafter.