Pergoveris Mechanism of Action

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, gonadotropins. ATC code: G03GA30.
Pharmacology: Pharmacodynamics: Pergoveris is a preparation of recombinant human follicle stimulating hormone (follitropin alfa, r-hFSH) and recombinant human luteinising hormone (lutropin alfa, r-hLH) produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.
Mechanism of action: Luteinising hormone (LH) and follicle stimulating hormone (FSH) are secreted from the anterior pituitary gland in response to gonadotropin-releasing hormone (GnRH) and play a complementary role in follicle development and ovulation. In theca cells, LH stimulates the secretion of androgens that are transferred to granulosa cells to be converted to oestradiol (E2) by aromatase. In granulosa cells, FSH stimulates the development of ovarian follicles, while LH action is involved in follicle development, steroidogenesis and maturation.
Pharmacodynamic effects: Inhibin and oestradiol levels are raised after administration of r-hFSH, with subsequent induction of follicular development. Inhibin serum level increase is rapid and can be observed as early as the third day of r-hFSH administration, while oestradiol levels take more time and an increase is observed only from the fourth day of treatment. Total follicular volume starts to increase after about 4 to 5 days of r hFSH daily dosing and, depending on patient response, the maximum effect is reached after about 10 days from the start of gonadotropin administration. The primary effect resulting from administration of r-hLH is a dose-related increase of E2 secretion, enhancing the effect of r-hFSH on follicular growth.
Clinical efficacy: 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%.
In one clinical study of women with hypogonadotropic hypogonadism and an endogenous serum LH concentration below 1.2 IU/L the appropriate dose of r-hLH was investigated. A dose of 75 IU r-hLH daily (in combination with 150 IU r-hFSH) resulted in adequate follicular development and oestrogen production. A dose of 25 IU r-hLH daily (in combination with 150 IU r-hFSH) resulted in insufficient follicular development.
Therefore, administration of Pergoveris containing less than 75 IU r-hLH daily may provide too little LH-activity to ensure adequate follicular development.
Pharmacokinetics: Clinical studies with Pergoveris were conducted with a freeze-dried formulation. A comparative clinical study between the freeze-dried and the liquid formulation showed bioequivalence between the two formulations.
There is no pharmacokinetic interaction between follitropin alfa and lutropin alfa when administered simultaneously.
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 14 to 17 hours. The steady state volume of distribution is in the range of 9 to 11 L.
Following subcutaneous administration, the absolute bioavailability is about 66% and the apparent terminal half-life is in the range of 24 to 59 hours. Dose proportionality after subcutaneous administration was demonstrated up to 900 IU. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steady-state within 3 to 4 days.
Elimination: Total clearance is 0.6 L/h and about 12% 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 9 to 11 hours. The steady state volume of distribution is in the range of 5 to 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 56%; and the apparent terminal half-life is in the range of 8 to 21 hours. Dose proportionality after subcutaneous administration was demonstrated up to 450 IU. The lutropin alfa pharmacokinetics following single and repeated administration of lutropin alfa are comparable and the accumulation ratio of lutropin alfa is minimal.
Elimination: Total clearance is in the range of 1.7 to 1.8 L/h, and less than 5% of the dose is excreted in the urine.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity.