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


METHODS
This was a first-in-human, double-blind, placebo-controlled, single- and multiple-dose study with sequential dose escalation.


METHODS
Fifty-five healthy, regularly cycling premenopausal women participated.


METHODS
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.


METHODS
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.
Struthers
R Scott
RS
Neurocrine Biosciences Inc., 12780 El Camino Real, San Diego, California 92130, USA. sstruthers@neurocrine.com
Nicholls
Andrew J
AJ
Grundy
John
J
Chen
Takung
T
Jimenez
Roland
R
Yen
Samuel S C
SS
Bozigian
Haig P
HP
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000097:blood / Q000378:metabolism*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006062:Gonadotropins / Q000097:blood / Q000378:metabolism*; D006066:Gonads / Q000187:drug effects / Q000378:metabolism; D006727:Hormone Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D010919:Placebos; D017697:Premenopause / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
D006062:Gonadotropins; D006727:Hormone Antagonists; D006845:Hydrocarbons, Fluorinated; D010919:Placebos; D011743:Pyrimidines; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; C539351:elagolix