Context: 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.

Design: This was a Phase I, double-blind, placebo-controlled, single-dose study with sequential dose-escalation.

Participants: Fifty-six healthy, post-menopausal women were included. FSH levels were greater than 40 IU/L and body mass index was within 20% of ideal values for all subjects.

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

Main Outcome Measures: 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. Maximum 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 following 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.