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
The contraceptive effect of Meliane is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion. Furthermore, the endometrium is rendered unreceptive to implantation.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

•      Gestodene
Orally administered gestodene is rapidly and completely absorbed. Following ingestion of a single Meliane tablet, maximum drug serum levels of about 3.5 ng/ml are reached at about 1.0 hour. Thereafter, gestodene serum levels decrease in two phases. The terminal disposition phase is characterised by a half-life of about 12 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 sex hormone binding globulin (SHBG). Only about 1.3% of the total serum drug levels are present as free steroid, but about 69% 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 to ca. 80 % while the unbound and the albumin- bound fraction decrease.
Following daily repeated administration of Meliane, an accumulation of gestodene concentration in the serum is observed. Mean serum levels are about fivefold higher at a steady-state, which is generally reached during the second half of a treatment cycle. The pharmacokinetics of gestodene are influenced by SHBG serum levels. Under treatment with Meliane a twofold 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 seem to change further.
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 a single Meliane tablet, maximum drug serum levels of about 65 pg/ml are reached at 1.7 hours.
Thereafter, ethinylestradiol serum levels decrease in two disposition phases, characterised by half-lives of about 2 hours and 21 hours, respectively. The terminal half-life of ethinylestradiol is subject to a large interindividual variation and a range of 5 to 30h has been reported in the literature. Due to 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 plasma of about 5 ml/min/kg were determined. Ethinylestradiol is highly but non-specifically bound to albumin. About 2 % of drug levels are present unbound.

During absorption and first-liver passage, ethinylestradiol is metabolized extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 20-65%. 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 of ethinylestradiol can be expected to be reached after 5 – 6 days. At the end of a treatment cycle, they were found to be higher by about 40-60% as compared to single dose administration.

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 corticoid binding globulin (CBG) 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 Meliane, SHBG concentrations in the serum increased from 107 nmol/l to 216 nmol/l in the first and to 223 nmol/l in the third cycle. Serum concentrations of CBG were increased from 42 µg/ml to 77 µg/ml in the first cycle and remained constant thereafter.