Suppression of Gonadotropins and Estradiol in Premenopausal Women by Oral Administration of the Nonpeptide GnRH Antagonist Elagolix Abbreviated Title: HPG Suppression by an Oral Nonpeptide GnRH Antagonist
ABSTRACT Context: Parenteral administration of peptide GnRH analogs is widely employed for treatment of endometriosis, fibroids and in assisted-reproductive therapy protocols. Elagolix is a novel, orally available nonpeptide GnRH antagonist. Objective: To evaluate the safety, pharmacokinetics and inhibitory effects on gonadotropins and estradiol of single dose and 7-day 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 pre-menopausal women. Interventions: Subjects were administered a single oral dose of 25 to 400 mg or placebo. In a second arm of the study, subjects received placebo or 50, 100, or 200 mg q.d. or 100 mg b.i.d. for seven days. Treatment was initiated on Day 7 (±1) following onset of menses. Main Outcome Measures: Safety, tolerability, pharmacokinetics and serum LH, FSH and estradiol concentrations. Results: Elagolix was well-tolerated and rapidly bioavailable following oral administration. Serum gonadotropins declined rapidly. Estradiol was suppressed by 24 hours in subjects receiving ≥ 50 mg/day. Daily (50 to 200 mg) or twice daily (100 mg) administration for 7 days maintained low estradiol levels (17 ± 3 pg/mL to 68 ± 46 pg/mL) in most subjects during late follicular phase. Effects of the compound were rapidly reversed following 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. HPG Suppression by an Oral Nonpeptide GnRH Antagonist
