Pituitary and gonadal endocrine effects and pharmacokinetics of the novel luteinizing hormone-releasing hormone antagonist teverelix in healthy men-a first-dose-in-humans study

Abstract

BACKGROUND. Teverelix is a novel synthetic peptidic luteinizing hormone-releasing hormone (LHRH) antagonist. Single subcutaneous morning doses of teverelix acetate (either 0.5, 1, 2, 3, or 5 mg base) were investigated in a randomized, single-blind, placebo-controlled, dose-escalating parallel-group design in healthy men. Six subjects received teverelix, and two subjects received placebo per dose level. Blood samples for lutropin, luteinizing hormone (LH), and follitropin, follicle-stimulating hormone (FSH), and testosterone, as well as for pharmacokinetics, were withdrawn up to 120 hours after dosing. Serum hormone levels were determined by electrochemicoluminescence immunoassays, and plasma teverelix concentrations were determined by radioimmunoassay. Teverelix led to a rapid, marked suppression of LH, testosterone and, to a lesser extent, FSH. Median maximum suppressions compared with predose levels were -93% for LH and -54% for FSH after teverelix 5 mg, and -93% for testosterone after teverelix 3 mg, respectively. After 5 mg teverelix, testosterone suppression <1 ng/mL started a median of 12 hours after dosing and lasted for a median of 33 hours. The duration of testosterone suppression increased with dose. Geometric means of peak teverilix plasma concentrations were 4.5 ng/mL (0.5 mg teverelix) to 49.0 ng/mL (5 mg teverelix) and tmax occurred between 1 and 4 hours after dosing. Geometric means of the area under the teverelix plasma concentration-time course from zero to time of the last quantifiable plasma concentration [AUC(O-tlast)] were 54.9 ng x h/mL (0.5 mg teverelix) to 881.8 ng x h/mL (5 mg teverelix). Median values for apparent terminal half-lives ranged from 24 to 75 hours. The most frequently reported adverse events were short-lasting mild injection-site reactions. Teverelix showed pronounced LH and testosterone suppressive effects after single subcutaneous doses in healthy men. Duration of hormone suppression increased with dose. Teverelix was well tolerated. This profile indicates potential for further clinical use.