Inhibition of substance P-mediated responses in NG108-15 cells by netupitant and palonosetron exhibit synergistic effects

Netupitant is a potent and selective NK1 receptor antagonist under development in combination with a fixed dose of palonosetron for the prevention of chemotherapy induced nausea and vomiting. Palonosetron is a 5-HT3 receptor antagonist approved for both the prevention of acute and delayed chemotherapy induced nausea and vomiting after moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), a ligand acting largely on tachykinin (NK1) receptors, is the dominant mediator of delayed emesis. Interestingly, palonosetron does not bind to the NK1 receptor so that the mechanism behind palonosetron's unique efficacy against delayed emesis is not clear. Palonosetron exhibits a distinct ability among 5-HT3 receptor antagonists to inhibit crosstalk between NK1 and 5-HT3 receptor signaling pathways. The objective of the current work was to determine if palonosetron's ability to inhibit receptor signaling crosstalk would influence netupitant's inhibition of the SP-mediated response when the two drugs are dosed together. We first studied the inhibition of SP-induced Ca2+ mobilization in NG108-15 cells by palonosetron, ondansetron and granisetron. Unexpectedly, in the absence of serotonin, palonosetron inhibited the SP-mediated dose response 15-fold; ondansetron and granisetron had no effect. Netupitant also dose-dependently inhibited the SP response as expected from an NK1 receptor antagonist. Importantly, when both palonosetron and netupitant were present, they exhibited an enhanced inhibition of the SP response compared to either of the two antagonists alone. The results further confirm palonosetron's unique pharmacology among 5-HT3 receptor antagonists and suggest that it can enhance the prevention of delayed emesis provided by NK1 receptor antagonists.