This study elucidates kinetic and dynamic properties of elagolix, an oral GnRH antagonist. Authors find that elagolix suppresses LH/FSH and Estradiol/Progestorone fully at respective doses of 300 mg and 200 mg BID. As expected the main side effects were hot flashes and headaches (induced menopausal symptoms). A group of 45 healthy premenopausal women were followed for 21 days.
Estrogen/ovarian suppression is needed in certain medical conditions such as hormone-dependent breast carcinomas.
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Context: Elagolix is an oral nonpeptide 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) or placebo was administered for 21 days.
Main Outcome Measures:
Main outcome measures were elagolix pharmacokinetics, gonadotropics (FSH and LH) and ovarian hormones (estradiol and progesterone) suppression and adverse events.
Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations at 1.0-1.5 hours, with a half-life of 4-6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on day one.
Dose-dependent suppression of estradiol 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, progesterone concentrations remained at anovulatory levels throughout 21 days of dosing.
The most frequently reported adverse events were headache and hot flush.
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.