Endocrine effects and pharmacokinetic characteristics of a potent new gonadotropin-releasing hormone antagonist (ganirelix) with minimal histamine-releasing properties: Studies in postmenopausal women

A potent and safe GnRH antagonist has been sought unsuccessfully for the last 2 decades. The recently developed GnRH antagonist RS-26306 or Ganirelix ([N-Ac-D-Nal(2)¹,D-pClPhe²,D-Pal(3) ³,D-hArg(Et₂)⁶,L-hArg(Et₂) ⁸,D-Ala¹⁰]GnRH; Syntex Research, Palo Alto, CA), exhibited high antiovulatory potency and low histamine-releasing properties in preclinical studies. Therefore, we determined the extent to which single sc injections of three doses of RS-26306 (1, 3, and 6 mg) decreased serum concentrations of LH and FSH, the free α-subunit of LH/FSH/TSH, PRL, and testosterone in five healthy postmenopausal women. We also examined the pharmacokinetic characteristics of RS-26306 by quantifying serum levels of the drug by RIA. RS-26306 rapidly suppressed serum concentrations of LH, FSH, and free α-subunit. RS-26306 (6 mg) maximally decreased serum concentrations (mean ± SEM) of LH, FSH, and free α-subunit by 70.1 ± 3.6%, 42.3 ± 2.5%, and 74.6 ± 3.5%, respectively. RS-26306 also decreased serum testosterone, but not serum PRL, concentrations. RS-26306 concentrations reached peak serum levels at 1.2 ± 0.3, 1.9 ± 0.4, and 1.8 ± 0.5 h, respectively, after 1-, 3-, and 6-mg sc injections. The mean serum half-life values based on the terminal portion of the disappearance curves were 22.8 ± 2.5 and 26.9 ± 1.0 h, respectively, after 3- and 6-mg s.c. doses. No systemic side-effects were noted after the administration of RS-26306. Our results demonstrate that the GnRH antagonist RS-26306 has favorable pharmacokinetic characteristics and is a potent suppressor of pituitary gonadotropin secretion in postmenopausal women. These attributes and the lack of systemic side-effects make RS-26306 a promising candidate for future clinical applications.