Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: progestogens and estrogens, fixed combinations, ATC code: G03AA09
Mercilon is an oral contraceptive combination containing 150 micrograms desogestrel and 20 micrograms ethinylestradiol.
Ethinylestradiol is a well-known synthetic estrogen.
Desogestrel is a synthetic progestogen. After oral administration it has a strong ovulation- inhibiting activity, a strong progestational and anti-estrogenic activity, no estrogenic activity, very weak androgenic/anabolic activity.


Paediatric population
No clinical data on efficacy and safety are available in adolescents below 18 years.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Desogestrel

Absorption

Orally administered desogestrel is rapidly and completely absorbed and converted to etonogestrel. Peak serum concentrations are reached at about 1.5 hours. Bioavailability is 62 - 81 %.


Distribution
Etonogestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). Only 2 -            4 % of the total serum drug concentrations are present as free steroid, 40 -70 % are specifically bound to SHBG. The ethinylestradiol-induced increase in SHBG influences the distribution over the serum proteins, causing an increase of the SHBG-bound fraction and a decrease of the albumin-bound fraction. The apparent volume of distribution of desogestrel is 1.5 l/kg.


Biotransformation
Etonogestrel is completely metabolized by the known pathways of steroid metabolism, including cytochrome P450 3A4. The metabolic clearance rate from serum is about            2 ml/min/kg. No interaction was found with the co-administered ethinylestradiol.


Elimination
Etonogestrel serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of approximately 30 hours. Desogestrel and its metabolites are excreted at a urinary to biliary ratio of about 6:4.


Steady-state conditions
Etonogestrel pharmacokinetics are influenced by SHBG levels, which are increased threefold by ethinylestradiol. Following daily ingestion, drug serum levels increase about two-to threefold, reaching steady state conditions during the second half of a treatment cycle.

Ethinylestradiol

Absorption
Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations are reached within 1-2 hours. Absolute bioavailability as a result of presystemic conjugation and first-pass metabolism is approximately 60%.


Distribution
Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98.5%) and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 5 l/kg was determined.


Biotransformation
Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The metabolic clearance rate is about 5 ml/min/kg.


Elimination
Ethinylestradiol serum levels decrease in two phases, the terminal disposition phase is characterized by a half-life of approximately 24 hours. Unchanged drug is not excreted; ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.


Steady-state conditions
Steady state concentrations are reached after 3-4 days when serum drug levels are higher by 30 - 40% as compared to single dose.