Netupitant and palonosetron trigger NK₁ receptor internalization in NG108-15 cells

Current therapy for chemotherapy-induced nausea and vomiting includes the use of both 5-HT₃ and NK₁ receptor antagonists. Acute emesis has largely been alleviated with the use of 5-HT₃ receptor antagonists, while an improvement in preventing delayed emesis has been achieved with NK₁ receptor antagonists. Delayed emesis, however, remains a problem with a significant portion of cancer patients receiving highly emetogenic chemotherapy. Like other drugs in its class, palonosetron, a 5-HT₃ receptor antagonist, has shown efficacy against acute emesis. However, palonosetron has also shown consistent improvement in the suppression of delayed emesis. Since both 5-HT₃ and NK₁ receptor antagonists are often simultaneously administered to patients, the question remains if palonosetron’s effect on delayed emesis would remain distinct when co-administered with an NK₁ receptor antagonist. Recent mechanistic studies using NG108-15 cells have shown that palonosetron and netupitant, an NK₁ receptor antagonist currently in phase 3 clinical trials, exhibited synergistic effects when inhibiting the substance P response. The present studies showed that both netupitant and palonosetron-induced NK₁ receptor internalization in NG108-15 cells and that when used together receptor internalization was additive. Palonosetron-induced NK₁ receptor internalization was dependent on the presence of the 5-HT₃ receptor. Results provide a possible explanation for palonosetron’s enhancement of the inhibition of the SP response and suggest that the effect of palonosetron and NK₁ receptor antagonists on prevention of delayed emesis could be additive.