Suppression of serum luteinizing hormone in postmenopausal women by an orally administered nonpeptide antagonist of the gonadotropin-releasing hormone receptor (NBI-42902).
BACKGROUND
Parenteral administration of peptide GnRH analogs is widely used in clinical practice for the suppression of pituitary gonadotropins. NBI-42902 is an orally available, high-affinity nonpeptide antagonist of the human GnRH receptor.


OBJECTIVE
The objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropin secretion of NBI-42902 in postmenopausal women.


METHODS
This was a phase I, double-blind, placebo-controlled, single-dose study with sequential dose escalation.


METHODS
Fifty-six healthy, postmenopausal women were included. FSH levels were greater than 40 IU/liter, and body mass index was within 20% of ideal values for all subjects.


METHODS
Subjects were administered 5, 10, 25, 50, 75, 100, 150, or 200 mg NBI-42902 as an oral solution.


METHODS
Safety, tolerability, and serum LH and FSH concentrations were evaluated.


RESULTS
NBI-42902 was well tolerated. Serum LH concentrations rapidly declined, and dose-dependent suppression was observed. Maximal change from baseline LH concentrations ranged from -19 +/- 5% in the 5-mg group to -55 +/- 2% in the 150-mg group. Suppression of FSH was less pronounced (-15 to -22% of baseline). NBI-42902 was rapidly absorbed after oral administration with a terminal elimination half-life ranging from 2.7 +/- 0.3 to 4.8 +/- 0.8 h. A clear relationship between plasma NBI-42902 concentrations and LH suppression was evident.


CONCLUSIONS
Dose-dependent LH suppression was achieved by oral administration of a nonpeptide GnRH antagonist suggesting that compounds such as NBI-42902 may enable adjustable gonadotropin suppression as part of novel treatment strategies for benign gynecological conditions.
Struthers
R Scott
RS
Department of Endocrinology, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA. sstruthers@neurocrine.com
Chen
TaKung
T
Campbell
Bruce
B
Jimenez
Roland
R
Pan
Henry
H
Yen
Samuel S C
SS
Bozigian
Haig P
HP
D000284:Administration, Oral; D000368:Aged; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors* / Q000097:blood; D008875:Middle Aged; D017698:Postmenopause / Q000097:blood*; D013941:Thymine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
C498569:3-(2-amino-2-phenylethyl)-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione; D007986:Luteinizing Hormone; D013941:Thymine