Ganirelix Other names: Ganirelix acetate Ganirelix diacetate

Ganirelix is a GnRH antagonist, which modulates the hypothalamic-pituitary-gonadal axis by competitive binding to the GnRH receptors in the pituitary gland. As a result a rapid, profound, reversible suppression of endogenous gonadotrophins occurs, without initial stimulation as induced by GnRH agonists.

Following administration of multiple doses of 0.25 mg ganirelix to female volunteers serum LH, FSH and E2 concentrations were maximally decreased by 74%, 32% and 25% at 4, 16 and 16 hours after injection, respectively. Serum hormone levels returned to pre-treatment values within two days after the last injection.

Pharmacodynamic effects

In patients undergoing controlled ovarian stimulation the median duration of ganirelix treatment was 5 days. During ganirelix treatment the average incidence of LH rises (>10 IU/L) with concomitant progesterone rise (>1 ng/mL) was 0.3-1.2% compared to 0.8% during GnRH agonist treatment. There was a tendency towards an increased incidence of LH and progesterone rises in women with a higher body weight (>80 kg), but no effect on clinical outcome was observed. However, based on the small number of patients treated so far, an effect cannot be excluded. In case of a high ovarian response, either as a result of a high exposure to gonadotrophins in the early follicular phase or as a result of high ovarian responsiveness, premature LH rises may occur earlier than day 6 of stimulation. Initiation of ganirelix treatment on day 5 can prevent these premature LH rises without compromising the clinical outcome.

Pharmacokinetic parameters after multiple subcutaneous dosing of ganirelix (once daily injection) were similar to those after a single subcutaneous dose. After repeated dosing 0.25 mg/day steady-state levels of approximately 0.6 ng/mL were reached within 2 to 3 days.

Pharmacokinetic analysis indicates an inverse relationship between body weight and serum concentrations of ganirelix.

Absorption

After a single subcutaneous administration of 0.25 mg, serum levels of ganirelix rise rapidly and reach peak levels (C_max) of approximately 15 ng/mL within 1 to 2 hours (t_max). The bioavailability of ganirelix following subcutaneous administration is approximately 91%.

Biotransformation

The major circulating component in plasma is ganirelix. Ganirelix is also the main compound found in urine. Faeces only contain metabolites. The metabolites are small peptide fragments formed by enzymatic hydrolysis of ganirelix at restricted sites. The metabolite profile of ganirelix in humans was similar to that found in animals.

Elimination

The elimination half-life (t_½) is approximately 13 hours and clearance is approximately 2.4 L/h. Excretion occurs via faeces (approximately 75%) and urine (approximately 22%).

Preclinical data reveal no special hazard for humans based on safety pharmacology, repeated dose toxicity and genotoxicity.

Reproduction studies carried out with ganirelix at doses of 0.1 to 10 μg/kg/day subcutaneously in the rat and 0.1 to 50 g/kg/day subcutaneously in the rabbit showed increased litter resorption in the highest dose groups. No teratogenic effects were observed.