Inhibiting Substance P Pathway for Prevention of Chemotherapy-Induced Emesis: Preclinical Data, Clinical Trials of Neurokinin-1 Receptor Antagonists

Abstract

Neurokinin-1 (NK-1) receptor antagonists are a new class of antiemetic agents that have activity in controlling cisplatin-induced acute and delayed emesis. Preclinical data in animal models show that the NK-1 receptor antagonists have broad antiemetic activity. The NK-1 receptor antagonists have activity in controlling emesis induced by peripherally acting and centrally acting emetogens, suggesting a mechanism of action at multiple sites. The effects at central and peripheral sites to control acute and delayed emesis cannot be determined at this time based on available studies. When added to a standard regimen of a 5-hydroxytryptamine-3 (5- HT3) receptor antagonist and dexamethasone, the NK-1 receptor antagonists improve control of acute emesis. The NK-1 receptor antagonists improve delayed emesis compared with placebo, and when used in combination with dexamethasone, compared with dexamethasone alone. Acute and delayed nausea may also be improved by the NK-1 receptor antagonists when they are used in combination with a 5-HT3 receptor antagonist and dexamethasone prechemotherapy or with daily dosing for 5 days after chemotherapy. The current data suggest that the mechanism of action of the NK-1 receptor antagonists appears to be different from that of the 5-HT3 receptor antagonists. Future studies may consider using NK-1 receptor antagonists with moderately emetogenic chemotherapy as well as bone marrow transplantation.