Acute and subchronic toxicity studies with detirelix, a luteinizing hormone-releasing hormone antagonist, in the rat and monkey.

Acute (single dose), 2-week, and 3-month toxicology studies were conducted with detirelix, a luteinizing hormone-releasing hormone (LHRH) antagonist, in rats and cynomolgus monkeys. Acute studies were conducted by intravenous and subcutaneous injection. Subchronic studies were conducted by daily subcutaneous injection. Clinical signs after a single intravenous dose included lethargy, edema, cyanosis, pallor, and red ears in rats at greater than or equal to 0.3 mg/kg and lethargy and facial flushing in monkeys at greater than or equal to 0.5 mg/kg. In subchronic studies, detirelix at greater than or equal to 0.4 mg/kg/day (rats) and at greater than or equal to 0.2 mg/kg/day (monkeys) produced atrophy of the reproductive organs, inhibition of ovulation and spermatogenesis, decreased body weight gain in male rats and monkeys, and increased body weight gain in female rats. In the rat, morbidity and/or mortality occurred throughout the treatment phase at a subcutaneous dose of greater than or equal to 2.0 mg/kg/day. In both species, the time to recovery of normal reproductive organ morphology and function was directly related to dose. Exogenous testosterone decreased the severity of reproductive and body weight effects in male rats. In conclusion, the acute effects of detirelix were consistent with peripheral vasodilation. Subchronic effects were associated with inhibition of pituitary gonadotropic and gonadal hormone secretion.