Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix.

Author(s): Struthers RS, Nicholls AJ, Grundy J, Chen T, Jimenez R, Yen SS, Bozigian HP

Affiliation(s): Neurocrine Biosciences Inc., 12780 El Camino Real, San Diego, California 92130, USA. sstruthers@neurocrine.com

Publication date & source: 2009-02, J Clin Endocrinol Metab., 94(2):545-51. Epub 2008 Nov 25.

Publication type: Clinical Trial, Phase I; Randomized Controlled Trial; Research Support, N.I.H., Extramural

CONTEXT: Parenteral administration of peptide GnRH analogs is widely employed for treatment of endometriosis and fibroids and in assisted-reproductive therapy protocols. Elagolix is a novel, orally available nonpeptide GnRH antagonist. OBJECTIVE: Our objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropins and estradiol of single-dose and 7-d elagolix administration to healthy premenopausal women. DESIGN: This was a first-in-human, double-blind, placebo-controlled, single- and multiple-dose study with sequential dose escalation. PARTICIPANTS: Fifty-five healthy, regularly cycling premenopausal women participated. INTERVENTIONS: Subjects were administered a single oral dose of 25-400 mg or placebo. In a second arm of the study, subjects received placebo or 50, 100, or 200 mg once daily or 100 mg twice daily for 7 d. Treatment was initiated on d 7 (+/-1) after onset of menses. MAIN OUTCOME MEASURES: Safety, tolerability, pharmacokinetics, and serum LH, FSH, and estradiol concentrations were assessed. RESULTS: Elagolix was well tolerated and rapidly bioavailable after oral administration. Serum gonadotropins declined rapidly. Estradiol was suppressed by 24 h in subjects receiving at least 50 mg/d. Daily (50-200 mg) or twice-daily (100 mg) administration for 7 d maintained low estradiol levels (17 +/- 3 to 68 +/- 46 pg/ml) in most subjects during late follicular phase. Effects of the compound were rapidly reversed after discontinuation. CONCLUSIONS: Oral administration of a nonpeptide GnRH antagonist, elagolix, suppressed the reproductive endocrine axis in healthy premenopausal women. These results suggest that elagolix may enable dose-related pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states.