Journal Article

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

Chwalisz, Kristof, Carter, David C., Ng, Juki, Klein, Cheri E.

2017

Overview

Context:Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone–dependent diseases in women.Objective:We evaluated the pharmacokinetics and pharmacodynamics of elagolix.Design, Setting, and Participants:This study was a 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 (BID)] or placebo was administered for 21 days.Main Outcome Measures:Main outcome measures were elagolix pharmacokinetics, suppression of gonadotropics [follicle-stimulating hormone (FSH), luteinizing hormone (LH)] and ovarian hormones [estradiol (E2), progesterone (P)], and adverse events.Results:Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations 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 BID. Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at 300 mg BID and 200 mg BID, respectively. At elagolix doses ≥100 mg BID, 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.Elagolix rapidly suppressed gonadotropins and ovarian sex hormones in healthy premenopausal women in a dose-dependent manner.

• Publisher: Endocrine Society,Oxford University Press
• Subject: 17β-Estradiol / Adult / Adverse events / Dosage / Dose-Response Relationship, Drug / Double-Blind Method / Estradiol - metabolism / Female / Follicle Stimulating Hormone - metabolism / Follicle-stimulating hormone / Gonadotropin-releasing hormone / Gonadotropin-Releasing Hormone - antagonists & inhibitors / Gonadotropins / Headache / Healthy Volunteers / Hormone Antagonists - pharmacology / Hormone replacement therapy / Hormones / Humans / Hydrocarbons, Fluorinated - pharmacology / Luteinizing hormone / Luteinizing Hormone - drug effects / Luteinizing Hormone - metabolism / Middle Aged / Ovaries / Pharmacodynamics / Pharmacokinetics / Pituitary (anterior) / Placebos / Premenopause / Progesterone / Progesterone - metabolism / Pyrimidines - pharmacology / Sex hormones / Soy products / Young Adult