Suppression of Serum Luteinizing Hormone in Postmenopausal Women by an Orally Administered Nonpeptide Antagonist of the Gonadotropin-Releasing Hormone Receptor (NBI-42902).
J Clin Endocrinol Metab. 2006 Jul 18
Struthers RS, Chen T, Campbell B, Jimenez R, Pan H, Yen SS, Bozigian HP.
Departments of Endocrinology, Preclinical Development, Clinical Development, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, California 92130; Department of Reproductive Medicine, University of California, San Diego.
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. |
