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: G03AA15

Mechanism of action
The continuous intake of Belara for 21 days inhibits pituitary FSH and LH secretion, and thus ovulation.
The endometrium proliferates and undergoes secretory transformation. The consistence of the cervical mucus is changed. This prevents sperm migration through the cervical canal and alters sperm motility.

The lowest daily dose of chlormadinone acetate for complete inhibition of ovulation is 1.7 mg. The full endometrial transformation dose is 25 mg per cycle.

Chlormadinone acetate is an antiandrogenic progestogen. Its effect is based on its ability to displace androgens from their receptors.

Clinical efficiency
In clinical studies in which the administration of film-coated tablets contain 0.03 mg ethinylestradiol and 2 mg chlormadinone acetate was tested for up to 2 years in 1,655 women and more than 22,000 menstruation cycles, there were 12 pregnancies. In 7 women the following factors were present during 18
 the period of conception: drug administration errors, concomitant diseases causing nausea or vomiting, 19 or concomitant administration of medicines known to reduce the contraceptive effect of hormonal contraceptives.

Method of use            Number of            Pearl index          95% confidence pregnancies                                   interval
Typical use                        12                     0.698           [0.389; 1.183] Perfect use                         5                     0.291           [0.115; 0.650] 

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Chlormadinone acetate (CMA)
Absorption
On oral administration CMA is rapidly and almost completely absorbed. The systemic bioavailability of CMA is high as it is not subject to first-pass metabolism. Peak plasma concentrations are reached after 1-2 hours.

Distribution
The binding of CMA to human plasma proteins, mainly albumin, is more than 95%. CMA has no binding affinity for SHBG or CBG. CMA is stored primarily in fatty tissue.

Biotransformation
Various reduction and oxidation processes and conjugation to glucuronides and sulphates result in a variety of metabolites. The principal metabolites in human plasma are 3α- and 3ß-hydroxy-CMA with biological half-lives that do not differ essentially from that of non-metabolised CMA. The 3-hydroxy metabolites show similar antiandrogenic activity as CMA itself. In the urine the metabolites appear mainly as conjugates. After enzymatic cleavage the main metabolite is 2α-hydroxy-CMA besides the 3- hydroxy-metabolites and dihydroxy metabolites.

Elimination
CMA is eliminated from the plasma with a mean half-life of about 34 hours (after a single dose) and about 36-39 hours (after multiple doses). After oral administration CMA and its metabolites are excreted both renally and in the faeces in about equal amounts.

Ethinylestradiol (EE)

Absorption
EE is rapidly and almost completely absorbed after oral administration and mean peak plasma concentrations are reached after 1.5 hours. Due to presystemic conjugation and first-pass metabolism in the liver the absolute bioavailability is only about 40% and is subject to considerable interindividual variation (20-65%).

Distribution
The EE plasma concentrations reported in the literature vary considerably. Approximately 98% of the EE is bound to plasma proteins, almost exclusively to albumin.

Biotransformation
Like natural oestrogens, EE is biotransformed via (cytochrome P-450 mediated) hydroxylation at the aromatic ring. The main metabolite is 2-hydroxy-EE, which is metabolised to other metabolites and conjugates. EE undergoes presystemic conjugation both in the mucosa of the small intestine and the liver. Mainly glucuronides are found in the urine, while mainly sulphates are found in the bile and plasma.

Elimination
The mean plasma half-life of EE is approximately 12-14 hours. EE is excreted via the kidneys and faeces in a ratio of 2:3. The EE sulphate excreted in the bile after hydrolysis by intestinal bacteria passes into the enterohepatic circulation.
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