Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT₃ receptor antagonists

• Published in: Cancer chemotherapy and pharmacology 2011-03, Vol.67 (3), p.667-686
• Main Authors: Percie du Sert, N, Rudd, J. A, Apfel, C. C, Andrews, P. L. R
• Format: Article
• Language: English
• Subjects: 5-HT₃ receptor antagonist; Animals; Antiemetics - administration & dosage; Antiemetics - pharmacology; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Biological and medical sciences; Cancer Research; cisplatin; Cisplatin - administration & dosage; Cisplatin - adverse effects; Disease Models, Animal; Dose-Response Relationship, Drug; Emesis; Ferrets; Granisetron; Humans; Medical sciences; Medicine; Medicine & Public Health; meta-analysis; Nausea - chemically induced; Nausea - prevention & control; Oncology; Ondansetron; Original; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Serotonin 5-HT3 Receptor Antagonists - administration & dosage; Serotonin 5-HT3 Receptor Antagonists - pharmacology; systematic review; Time Factors; Tropisetron; Vomiting - chemically induced; Vomiting - prevention & control
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-010-1339-4

Purpose The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT₃ receptor antagonists to assess its translational validity. Methods A systematic review identified available evidence and was used to perform meta-analyses. Results Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg⁻¹ dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg⁻¹, which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT₃ receptor antagonists reduced cisplatin (5 mg kg⁻¹) emesis by 68% (45-91%) during the acute phase (day 1) and by 67% (48-86%) and 53% (38-68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. Conclusion Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT₃ receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret.