The Potential Role for Corticosterone in the Induction of Cleft Palate in Mice After Treatment With a Selective NK‐1 Receptor Antagonist, Casopitant (GW679769B)

Abstract

Casopitant is a potent and selective NK-1 receptor antagonist that has shown clinical efficacy in the prevention of chemotherapy-induced and postoperative-induced nausea and vomiting. In an embryo-fetal development study, pregnant mice were given vehicle (sterile water) or doses of 30, 100, or 300 mg/kg/day casopitant on Gestation Day (GD) 6 to 15. Fetuses were evaluated for external, visceral, and skeletal abnormalities on GD 18. In a follow-on study to investigate casopitant-induced hormonal changes during the developmental period for palate formation, pregnant mice were given vehicle (sterile water) or 300 mg/kg/day casopitant once daily on GD 6 to 13. Blood was collected on GD 13 at various time-points for measurement of plasma adrenocorticotropic hormone and corticosterone (CRT) concentrations. There was no evidence of developmental toxicity in mice at 30 or 100 mg/kg/day but 9% of fetuses at 300 mg/kg/day had cleft palate. Mice are sensitive to glucocorticoid-induced cleft palates, and NK-1 antagonists are known to modulate the hypothalamic-pituitary-adrenal axis leading to increases in corticosterone. On GD 13, mean plasma adrenocorticotropic hormone levels at 300 mg/kg/day were elevated by approximately twofold from vehicle-treated levels at 1 hr post-dose and mean plasma CRT levels were elevated by 3, 5, and 10-fold at 0.5, 1, and 2 hr post-dose, respectively. The increased level of CRT was in the range previously shown in the literature to cause cleft palates in mice and was likely the underlying mechanism behind casopitant-induced cleft palate in mice.