Anti-nausea effects and pharmacokinetics of ondansetron, maropitant and metoclopramide in a low-dose cisplatin model of nausea and vomiting in the dog: A blinded crossover study

Abstract

Background: Nausea is a subjective sensation which is difficult to measure in non-verbal species. The aims of this study were to determine the efficacy of three classes of antiemetic drugs in a novel low dose cisplatin model of nausea and vomiting and measure change in potential nausea biomarkers arginine vasopressin (AVP) and cortisol. A four period cross-over blinded study was conducted in eight healthy beagle dogs of both genders. Dogs were administered 18mg/m2 cisplatin intravenously, followed 45min later by a 15min infusion of either placebo (saline) or antiemetic treatment with ondansetron (0.5mg/kg; 5-HT3 antagonist), maropitant (1mg/kg; NK1 antagonist) or metoclopramide (0.5mg/kg; D2 antagonist). The number of vomits and nausea associated behaviours, scored on a visual analogue scale, were recorded every 15min for 8h following cisplatin administration. Plasma samples were collected to measure AVP, cortisol and antiemetic drug concentrations. Results: The placebo treated group vomited an average number of 7 times (range 2-13). None of the dogs in either the ondansetron or maropitant treated groups vomited during the observation period. The onset of nausea-like behaviour in the placebo-treated group occurred at t3.5h and peaked at t4.75h with nausea behaviour score of 58.5±4.6mm. Ondansetron and maropitant reduced overall the area under the curve of nausea behaviour score by 90% and 25%, respectively. Metoclopramide had no effect on either vomiting or nausea. Cisplatin-induced nausea and vomiting caused concomitant increases in AVP and cortisol. In the placebo-treated group, AVP and cortisol increased from t2.5h, peaked at t5h (11.3±2.9pmol L-1 and 334.0±46.7nmol/L, respectively) and returned to baseline by t8h. AVP and cortisol increases were completely prevented by ondansetron and only partially by maropitant, while metoclopramide had no effect. The terminal half-lives (harmonic mean±pseudo SD) for ondansetron, maropitant and metoclopramide were 1.21±0.51, 5.62±0.77 and 0.87±0.17h respectively. Conclusions: 5-HT3 receptor antagonist ondansetron demonstrates the greatest anti-emetic and anti-nausea efficacy of the three drugs. AVP and cortisol appear to be selective biomarkers of nausea rather than emesis, providing a means of objectively measuring of nausea in the dog.