Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, gonadotropins. ATC code: G03GA30.

Pergoveris is a preparation of follicle stimulating hormone and luteinising hormone produced by genetically engineered Chinese Hamster Ovary (CHO) cells.

Mechanism of action

In clinical trials the efficacy of the combination of follitropin alfa and lutropin alfa has been demonstrated in women with hypogonadotropic hypogonadism.

In the stimulation of follicular development in anovulatory women deficient in LH and FSH, the primary effect resulting from administration of lutropin alfa is an increase in oestradiol secretion by the follicles, the growth of which is stimulated by FSH.

Pharmacodynamic effects

In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/l as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories. In these trials the ovulation rate per cycle was 70-75%.
Clinical efficacy

In one clinical study of women with hypogonadotrophic hypogonadism and an endogenous serum LH concentration below 1.2 IU/l the appropriate dose of r-hLH (lutropin alfa) was investigated. A dose of 75 IU r-hLH daily (in combination with 150 IU follitropin alfa (r- hFSH)) resulted in adequate follicular development and oestrogen production. A dose of 25 IU r-hLH daily (in combination with 150 IU follitropin alfa) resulted in insufficient follicular development. Therefore, administration of less than one vial of Pergoveris daily may provide too little LH-activity to ensure adequate follicular development.

Pharmacokinetic Properties

5.2       Pharmacokinetic properties

Follitropin alfa and lutropin alfa have shown the same pharmacokinetic profile as follitropin alfa and lutropin alfa separately.

Follitropin alfa

Distribution
Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution is 10 l.
Following subcutaneous administration, the absolute bioavailability is about 70%.
Following repeated administration, follitropin alfa accumulates 3-fold achieving a steady-state within 3-4 days. In women whose endogenous gonadotrophin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.

Elimination
Total clearance is 0.6 l/h and one-eighth of the follitropin alfa dose is excreted in the urine.

Lutropin alfa
Distribution
Following intravenous administration, lutropin alfa is rapidly distributed with an initial half-life of approximately one hour and eliminated from the body with a terminal half-life of about 10-12 hours. The steady state volume of distribution is around 10-14 l. Lutropin alfa shows linear pharmacokinetics, as assessed by AUC which is directly proportional to the dose administered.
Following subcutaneous administration, the absolute bioavailability is approximately 60%; the terminal half-life is slightly prolonged. The lutropin alfa pharmacokinetics following single and repeated administration of lutropin alfa are comparable and the accumulation ratio of lutropin alfa is minimal. The mean residence time is approximately 5 hours.
Elimination
Total clearance is around 2 l/h, and less than 5% of the dose is excreted in the urine.

Pharmacokinetic/pharmacodynamic relationships
There is no pharmacokinetic interaction with follitropin alfa when administered simultaneously.