Study Sheds Light on How Palonosetron Prevents Delayed CINV

Palonosetron is the only 5-HT₃ receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) following administration of moderately emetogenic chemotherapeutic agents. At a platform presentation held during the 6th Annual Hematology/Oncology Pharmacy Association (HOPA) Meeting, Barbara S. Slusher, PhD, chief scientific officer, Brain Science Institute, NeuroTranslational Program, Johns Hopkins School of Medicine, Baltimore, Maryland, presented the results of a study that used in vitro and in vivo approaches to determine why palonosetron is effective in preventing delayed CINV compared with other agents. Slusher and colleagues postulated that palonosetron differentially inhibits “crosstalk” between NK-1 receptors and 5-HT₃ signaling pathways. Previous studies have suggested that substance P (SP) acting on NK-1 receptors is the dominant mediator of delayed emesis, with recent data revealing significant “crosstalk” between the NK-1 receptors and 5-HT₃ signaling pathways.

In vitro assessment

For the in vitro assessment, NG108-15 cells were preincubated with palonosetron, granisetron, or ondansetron. After these antagonists were removed, Slusher and colleagues measured SP-induced calcium-ion release in the NG108-15 cells. They found that palonosetron inhibited the serotonin enhancement of SP-induced calcium-ion release whereas the other antiemetics did not.

In vivo assessment

For the in vivo assessment, rats treated with cisplatin were given palonosetron, granisetron, or ondansetron. After stimulation with SP, single neuronal recordings of nodose ganglia expressing both NK-1 and 5HT₃ receptors were collected.Slusher and colleagues found that cisplatin significantly enhanced neuronal responses to SP. Palonosetron dose-dependently inhibited the SP enhancement caused by the cisplatin when palonosetron was administered 30 minutes before or 5 or 10 hours following administration of cisplatin. Granisetron and ondansetron did not inhibit the cisplatin-induced SP enhancement.

Conclusions

According to Slusher, this is the first study to show that palonosetron inhibits SP-induced calcium-ion release in vitro as well as SP-induced neuronal responses in vivo. These findings may help explain the unique efficacy observed with palonosetron versus granisetron and ondansetron in the setting of delayed CINV.