Dose-Dependent Suppression of Gonadotropins and Ovarian Hormones by Elagolix in Healthy Premenopausal Women

Abstract

Context: Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone dependent diseases in women. Objective: To evaluate the pharmacokinetics and pharmacodynamics of elagolix. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit. Interventions: Elagolix 150 mg once daily or 100, 200, 300 or 400 mg twice daily or placebo for 21 days. Main Outcome Measures: Elagolix pharmacokinetics; suppression of gonadotropics (follicle-stimulating hormone [FSH], luteinizing hormone [LH]), and ovarian hormones (estradiol [E2], progesterone [P]); adverse events. Results: Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations (C_max) at 1.0 to 1.5 hours, with a half-life of 4 to 6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on Day 1. Dose-dependent suppression of E2 was observed, with maximum suppression achieved with elagolix 200 mg twice daily. Dose-dependent suppression of FSH and LH was also observed, with maximal or near maximal suppression achieved at 300 mg twice daily and 200 mg twice daily, respectively. At elagolix doses ≥ 100 mg twice daily, P concentrations remained at anovulatory levels throughout 21 days of dosing. The most frequently reported adverse events were headache and hot flush. Conclusions: Elagolix administration allows for modulation of gonadotropin and ovarian hormone concentrations, from partial suppression at lower doses to nearly full suppression at higher doses. The results of this study provide a rationale for elagolix dose selection for treatment of sex hormone-dependent diseases in women.