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.