Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: OTHER SEX HORMONE AND MODULATOR OF THE REPORDUCTIVE FUNCTION/ANTIPROGESTOGEN
ATC code: GO3 X B01

Mifepristone is a synthetic steroid with an antiprogestational action as a result of competition with progesterone at the progesterone receptors.

At doses ranging from 3 to 10 mg/kg orally, it inhibits the action of endogenous or exogenous progesterone in different animal species (rat, mouse, rabbit and monkey). This action is manifested in the form of pregnancy termination in rodents.

In women at doses greater than or equal to 1 mg/kg, mifepristone antagonises the endometrial and myometrial effects of progesterone. During pregnancy it sensitises the myometrium to the contraction- inducing action of prostaglandins. During the first trimester, pre-treatment with mifepristone allows the dilation and opening of the cervix uteri. While clinical data have demonstrated that mifepristone facilitates dilatation of the cervix, no data is available to indicate that this results in a lowering of the rate of early or late complications to the dilatation procedure.

In the event of an early termination of pregnancy, the combination of a prostaglandin analogue used in a sequential regimen after mifepristone leads to an increase in the success rate to about 95 per cent of the cases and accelerates the expulsion of the conceptus.

In clinical trials, according to the prostaglandin used and the time of application, the results vary slightly.

The success rate is around 95% when 600 mg mifepristone is combined with misoprostol 400 μg orally up to 49 days of amenorrhea, and with gemeprost applied vaginally, it reaches 98% up to 49 days of amenorrhea and 95% up to 63 days of amenorrhea.

According to the clinical trials and to the type of prostaglandin used, the failure rate varies. Failures occur in 1.3 to 7.5% of the cases receiving sequentially MIFEGYNE® followed by a prostaglandin analog, of which;

-    0 to 1.5% of ongoing pregnancies
-    1.3 to 4.6% of partial abortion, with incomplete expulsion
-    0 to 1.4% of hemostatic curettages

In pregnancies up to 49 days of amenorrhea, comparative studies between 200 mg and 600 mg of mifepristone in combination with 400 μg misoprostol orally cannot exclude a slightly higher risk of continuing pregnancies with the 200 mg dose.

In pregnancies up to 63 days of amenorrhea, comparative studies between 200 mg and 600 mg of mifepristone in combination with 1 mg gemeprost vaginally suggest that 200 mg mifepristone may be as effective as 600 mg mifepristone:
• Complete abortion rates with 200 mg and 600 mg were 93.8% and 94.3%, respectively, in women with < 57 days of amenorrhea (n=777. WHO 1993), and 92.4% and 91.7%, respectively, in women with 57 to 63 days of amenorrhea (n=896, WHO 2001).
•   Rates of ongoing pregnancies with 200 mg and 600 mg were 0.5% and 0.3%, respectively, in women with < 57 days of amenorrhea, and 1.3% and 1.6%, respectively, in women with 57 to 63 days of amenorrhea.

Combination of Mifepristone with prostaglandin analogues other than misoprostol and gemeprost have not been studied.

During the termination of pregnancy for medical reasons, beyond the first trimester,. mifepristone administered at a 600-mg dose, 36 to 48 hours prior to the first administration of prostaglandins, reduces the induction-abortion interval, and also decreases the prostaglandin doses required for the expulsion.

When used for labour induction of foetal death in utero, mifepristone alone induces expulsion in about 60% of cases within 72 hours following the first intake. In that event, the administration of prostaglandin or ocytocics would not be required.

Mifepristone binds to the glucocorticoid receptor. In animals at doses of 10 to 25 mg/kg it inhibits the action of dexamethasone. In man the antiglucocorticoid action is manifested at a dose equal to or greater than 4.5 mg/kg by a compensatory elevation of ACTH and cortisol. Glucocorticoid bioactivity (GBA) may be depressed for several days following a single administration of 200 mg mifepristone for termination of pregnancy. The clinical implications of this are unclear, however vomiting and nausea may be increased in susceptible women.

Mifepristone has a weak anti-androgenic action which only appears in animals during prolonged administration of very high doses.

Pharmacokinetic Properties

5.2 PHARMACOKINETIC PROPERTIES

Absorption
After oral administration of a single dose of 600 mg mifepristone is rapidly absorbed. The peak concentration of 1.98 mg/l is reached after 1.30 hours (means of 10 subjects).

After oral administration of low doses of mifepristone (20 mg), the absolute bioavailability is 69%).

Distribution
In plasma mifepristone is 98% bound to plasma proteins: albumin and principally alpha-1-acid glycoprotein (AAG), to which binding is saturable. Due to this specific binding, volume of distribution and plasma clearance of mifepristone are inversely proportional to the plasma concentration of AAG.

Biotransformation
N-Demethylation and terminal hydroxylation of the 17-propynyl chain are primary metabolic pathways of hepatic oxidative metabolism.

Elimination
There is a non-linear dose response. After a distribution phase, elimination is at first slow, the concentration decreasing by a half between about 12 and 72 hours, and then more rapid, giving an elimination half-life of 18 hours. With radio receptor assay techniques, the terminal half-life is of up to 90 hours, including all metabolites of mifepristone able to bind to progesterone receptors.

Mifepristone is mainly excreted in faeces. After administration of a 600 mg labelled dose, 10% of the total radioactivity is eliminated in the urine and 90% in the faeces.