Single and multiple dose pharmacokinetics and pharmacodynamics of the gonadotrophin-releasing hormone antagonist Cetrorelix in healthy female volunteers

Abstract

The gonadotrophin-releasing hormone antagonist Cetrorelix is in advanced clinical development for the control of endogenous gonadotrophin secretion during the course of a fertility programme. The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of Cetrorelix following single and multiple s.c. administration of different doses. Thirty-six healthy female volunteers received either 0.25, 0.50 or 1.00 mg Cetrorelix, in a first menstrual cycle as single dose and in a second cycle as multiple dose (daily between cycle days 3 and 16). Frequent blood samples were collected for determination of Cetrorelix, follicle stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and progesterone concentrations. Follicular growth was measured by transvaginal ultrasonography. After single administration of each dose, maximum Cetrorelix concentrations (Cmax) were reached after 1 h, and Cmax and area under curve (AUC) increased linearly with the dose. The median terminal half-life ranged from 5 to 10 h in the three different dose groups. FSH, LH, oestradiol and progesterone concentrations were suppressed, with a nadir at 6-12 h after Cetrorelix administration. During multiple administration, Cmax and AUC also showed dose-linearity. The median terminal half-life of Cetrorelix varied between 20 and 80 h. A dose-dependent suppression of FSH, LH and oestradiol concentrations was observed during treatment. After multiple administration, ovulation was delayed for 5, 10 and 13 days in the 0.25, 0.50 and 1.00 mg dose groups, respectively. In conclusion, Cetrorelix showed linear pharmacokinetics, and effectively delayed the LH surge.

Timing and duration of use of GnRH antagonist down-regulation for IVF/ICSI cycles have no impact on oocyte quality or pregnancy outcomes

“…GnRH antagonists would decrease the effect of endometrial growth factors and thus alter oocyte development and decrease endometrial receptivity. The half-life of GnRHantagonists is about 30 h, and embryo transfer is usually performed on day 3 after retrieval [8]. Therefore, the hypothesized effect on the endometrium could still persist at the time of embryo implantation.…”

Comparison of the effects of two GnRH antagonists on LH and FSH secretion, follicular growth and ovulation in the mare

“…The data of two studies can be used to compare the pharmacokinetics of Antarelix and Cetrorelix: in humans, after subcutaneous administration of 0.01 mg . kg -1 of Antarelix [15] or Cetrorelix [14], the terminal half-life is longer for Antarelix (23 h) than for Cetrorelix (10 h). But these results must be used 261 cases, when antagonists have a delaying effect of 1 to 3 days on the LH surge and ovulation, this surge often attenuated, is observed after the end of the treatment [24].…”

Hypothalamic gonadotropin-releasing hormone (GnRH) receptor neurons fire in synchrony with the female reproductive cycle

“…itary, thereby also reducing the rate of ovulation (Duijkers et al 1998;Reissmann et al 2000). To test whether systemic subcutaneous cetrorelix treatment is capable of influencing the GnRH/GnRHR signaling of Pe neurons, we injected 0.9% sodium chloride (sham-treatment group), or 10 g or 50 g of cetrorelix into mice daily for 9 days, starting at either metestrus or diestrus for all groups (Fig.…”