Abstract 593: Ocular drops of palonosetron reduce chemotherapy-induced acute nausea and vomiting in the dog

Abstract

Abstract Background: Nausea and vomiting are common side effects of cancer therapies thereby seriously affecting the quality of life of patients. Therefore, the prevention or treatment of chemotherapy-induced nausea and vomiting has become an important part of the comprehensive treatment of cancer. Several 5-HT3 receptor antagonists have been developed in the treatment of nausea and vomiting using mainly the oral route of administration (which is not convenient due to vomiting) or the intravenous route. In this study we tested whether ocular administration of the 5-HT3 receptor antagonist palonosetron (eye drops) could prevent nausea and vomiting associated with intravenous cisplatin injection in dogs. Methods: Six adult male Beagle dogs (10-13 kg) were included in a randomized crossover study. This study was carried out in AAALAC facilities in strict accordance with the European and French animal welfare regulations for animal use in experimentation. Dogs were administered 18 mg/m2 cisplatin intravenously over a 20-min period, followed 45 min later by ocular administration (eye drops, 200µL/eye) of either placebo (2% povidone in saline) or palonosetron (30 or 120 µg/kg). The number of vomits and nausea associated behaviours, scored on a visual analogue scale (VAS), were recorded every 15 min for 7 h following cisplatin administration. Blood samples were collected to measure plasma levels of palonosetron. Results: The placebo treated group vomited an average number of 10.2±2.1 times (range 5-17) over the 7-h period following cisplatin infusion. Ocular administration of palonosetron at 30 μg/kg in cisplatin-treated dogs very strongly and significantly decreased vomiting episodes, with only 1 vomiting episode in 2 dogs overall (p<0.0001). After ocular administration of palonosetron at 120 μg/kg, no vomiting episodes were observed in any dog throughout the observation period (p<0.0001). With regards to the VAS, in the placebo-treated group the nausea-associated behaviour started between 2.5 and 2.75 h after the end of the cisplatin infusion and peaked between 3.75 and 4.25 h after the end of the cisplatin infusion. The area under the curve (AUC) of VAS was 7344 ± 1050 mm*min in the placebo-treated group. Ocular administration of palonosetron at 30 or 120 µg/kg in cisplatin-treated dogs decreased the VAS score strongly. The VAS AUCs were 320 ± 268 (p<0.0001) and 0 ± 0 mm*m (p<0.0001) in 30 µg/kg and 120 µg/kg palonosetron groups, respectively. Plasma palonosetron concentration reached 10.3 ± 3.9 ng/mL, 5 min after ocular administration of palonosetron at 30 µg/kg and 2.8 ± 0.5 ng/mL and 0.9 ± 0.2 ng/mL at 2 h and 6 h post dosing, respectively. Conclusions: This study demonstrates for the first time that palonosetron administered via ocular route produces a rapid clear-cut anti-emetic and anti-nausea effect in conscious dogs exposed to cisplatin. This finding points out the tremendous interest of this novel and convenient route of administration which could help improving the quality of life of patients. Citation Format: Sandra Nourry, Minja Hyttila-Hopponen, Pierre Montagne, Lasse Saloranta, Sari Pappinen, Jouko Levijoki, Christophe Drieu La Rochelle. Ocular drops of palonosetron reduce chemotherapy-induced acute nausea and vomiting in the dog [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 593.