18608 Background: As monotherapies, ondansetron (a 5HT3 receptor antagonist) and casopitant mesylate ( GW679769 ) are effective anti-emetics in models of chemotherapy-induced nausea and vomiting in the ferret. To demonstrate the potential benefit of combination therapy, suboptimal doses of both ondansetron and casopitant mesylate were administered to ferrets receiving cisplatin. Methods: A 4x4 factorial design was utilized to test for therapeutically synergistic anti-emetic activity. Suboptimal doses (administered as monotherapy, which reduced vomiting and retching by >50% compared to control ferrets but did not result in complete protection) of each compound alone and in combination (0.3, 0.1, and 0.03 mg/kg) were administered 25 minutes prior to injection with cisplatin (10 mg/kg, IP). All emetic events/behaviors were recorded digitally via camera and DVR. Normal behaviors (eating, drinking, urination, defecation), emetic events (vomits, retches), and peri-emetic events (excessive mouth licking, burrowing, eye squinting, backward walking, and body scratching) were recorded temporally. All events were analyzed by finding the cumulative sum of events over time. Therapeutic synergy calculations were determined by analysis of variance. Results: Analysis of emetic events demonstrated the combination of ondansetron and casopitant mesylate resulted in significantly fewer events than either agent alone. Similar activity was demonstrated for vomits, retches, event latency, duration of emesis, water intake, food intake, and complete response. Conclusions: Co-administration of ondansetron and casopitant mesylate results in therapeutically synergistic anti-emetic and potential anti-nausea activity in this cisplatin-induced emesis model in ferrets. Pharmacokinetic analysis indicated no alteration of disposition of either agent. Therefore, we believe the synergy observed between ondansetron and casopitant mesylate is the result of their complementary mechanisms of pharmacologic action. Casopitant mesylate is currently in phase III trials for the prevention of PONV and CINV from moderately and highly emetogenic chemotherapy. It is also in clinical development for depression and anxiety. [Table: see text]