Regulon Mechanism of Action

Pharmacotherapeutic group: Hormonal contraceptives for systemic use; Progestogens and estrogens, fixed combinations. ATC code: G03AA09.
Pharmacology: Pharmacodynamics: Mechanism of action: The contraceptive action of CHCs is based on interaction of different factors, out of which the most important is the inhibition of ovulation and changes in the cervical secretion. Besides protection against pregnancy, CHCs have several positive properties which, next to the negative properties (see Precautions and Adverse Reactions), can be useful in deciding on the method of birth control. The cycle is more regular and the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency. Also it seems that the risk of endometrial cancer and ovarian cancer is reduced. Furthermore, it has been shown that high dosed combined hormonal contraceptives (50 microgram ethinylestradiol) reduce the risk of ovarian cysts, pelvic inflammatory disease, benign breast disorders, ectopic pregnancy and endometrial and ovarian cancer. Whether this also is the case for low dose combined hormonal contraceptives is not yet confirmed.
Paediatric population: No clinical data on efficacy and safety are available in adolescents below 18 years.
Pharmacokinetics: Desogestrel: Absorption: Orally administered desogestrel is rapidly and completely absorbed and converted to etonogestrel.
Following ingestion of a single dose, peak serum concentrations of about 2 ng/mL are reached within 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 of 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. 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 is 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. Following ingestion of a single dose, peak serum concentrations of about 80 pg/mL 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. In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism based inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.
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.