Summary
Insight into the pathophysiology of antineoplastic therapy-induced nausea and vomiting led to the development of the serotonin 5-HT3 receptor antagonists as the most potent class of antiemetic agents. Among those which have been investigated are ondansetron, granisetron, tropisetron and dolasetron. A riskbenefit analysis of these drugs must not only account for the modest clinical differences in efficacy and tolerability, but also should include such issues as ease of use, route of administration, dosage considerations and patient preference.
Pharmacokinetic and preclinical studies reveal distinctions among these antiemetics, but, overall, these distinctions do not translate in to clinically significant differences. In clinical trials, the most widely studied members of the 5-HT3 receptor antagonists are granisetron and ondansetron, which have been found to possess equivalent antiemetic efficacy. Dolasetron and tropisetron are also available, and some randomised trials have also documented their similar antiemetic activity, depending on the doses and schedules used. The equivalent efficacy of oral granisetron 2mg versus intravenous ondansetron 32mg has recently been demonstrated in prospective randomised clinical trials in patients receiving either highly emetogenic or moderately emetogenic antineoplastic therapy. The utilisation and efficacy of oral ondansetron and dolasetron in patients receiving moderately emetogenic antineoplastic therapy has also been documented.
This review offers a brief overview of the pharmacokinetic and preclinical research on the 5-HT3 antagonists, a review of the comparative clinical trials of the major members of this class and a summary risk-benefit assessment that considers clinical applicability and cost, as well as efficacy and safety.
Similar content being viewed by others
References
Perez EA, Gandara DR. Advances in the control of chemotherapy-induced emesis. Ann Oncol 1992; 3 Suppl. 3: S47–50
Del Favero A, Roila F, Tonato M. Reducing chemotherapy-induced nausea and vomiting: current perspectives and future possibilities. Drug Saf 1993; 9(6): 410–28
Aapro MS. Controlling emesis related to cancer therapy. Eur J Cancer 1991; 27(3): 356–61
Fozard JR. MDL 72222: a potent and highly selective antagonist of neuronal 5-hydroxytryptamine receptors. Naunyn Schmiedebergs Arch Pharmacol 1984; 326: 36
Miner WD, Sanger GJ. Inhibition of cisplatin-induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism. Br J Pharmacol 1986; 88: 497–9
Miner WD, Sanger GJ, Turner DH. Evidence that 5-hydroxytryptamine3 receptors mediate cytotoxic drug and radiationevoked emesis. Eur J Cancer 1987; 56: 159–62
Miner WD, Sanger GJ, Turner DH. Comparison of the effect of BRL 24924, metoclopramide and domperidone on cis-platininduced emesis in the ferret. Br J Pharmacol Proc 1986; Suppl. 88: 374P
Aapro MS. 5-HT3 receptor antagonists: An overview of their present status and future potential in cancer therapy-induced emesis. Drugs 1991; 42(4): 551–68
Blower PR. Comparative pharmacology of 5-HT3 receptor antagonists. Hosp Formul 1994; 29 Suppl. 5: S4–9
Schworer H, Racke K, Kilbinger H. Cisplatin increases the release of 5-hydroxytryptamine (5-HT) from the isolated vascularly perfused small intestine of the guinea-pig: Involvement of 5-HT3 receptors. Naunyn Schmiedebergs Arch Pharmacol 1991; 344: 143–49
Gebauer A, Merger M, Kilbinger H. Modulation by 5-HT3 and 5-HT4 receptors of the release of 5-hydroxytryptamine from the guinea pig small intestine. Naunyn Schmiedebergs Arch Pharmacol 1993; 347: 137–40
Perez EA. Review of the preclinical pharmacology and comparative efficacy of 5-hydroxytryptamine-3 receptor antagonists for chemotherapy-induced emesis. J Clin Oncol 1995; 13(4): 1036–43
Kytril (granisetron hydrochloride injection) prescribing information. Philadelphia: SmithKline Beecham Pharmaceuticals, Aug, 1995
Zofran (ondansetron hydrochloride injection) prescribing information. Cerenex Pharmaceuticals, Division of Glaxo Wellcome, Aug, 1993
Lee CR, Plosker GL, McTavish D. Tropisetron: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as an antiemetic. Drugs 1993; 46: 925–43
Miller RC, Galvan M, Gittos MW, et al. Pharmacological properties of dolasetron, a potent and selective antagonist at 5-HT3 receptors. Drug Dev Res 1993; 28: 87–93
Audhuy B, Cappelaere P, Martin M, et al. A double-blind, randomized comparison of the anti-emetic efficacy of two intravenous doses of dolasetron mesilate and granisetron in patients receiving high-dose cisplatin chemotherapy. Eur J Cancer 1996; 32A(5): 807–13
Galvan M, Claverie N, Hahne W. Pharmacology and metabolism of dolasetron mesilate. European Hospital Pharmacy 1996; 2 Suppl. 1: S12–4
Andrews PLR, Bhandari P, Davey PT, et al. Are all 5-HT3 receptor antagonists the same? Eur J Cancer 1992; 28A Suppl. 1: S2–6
Van Wijngaarden I, Tulp MThM, Soudijn W. The concept of selectivity in 5-HT receptor research. Eur J Pharm Mol Pharmacol 1990; 188: 301–12
Newberry NR, Watkins CJ, Sprosen TS, et al: BRL 46470 potently antagonizes neural responses activated by 5-HT3 receptors. Neuropharmacology 1993; 32: 729–35
Chevallier B, Bleiberg H, Fauser AA, et al. Dolasetron in the control of chemotherapy-induced nausea and vomiting. European Hospital Pharmacy 1996; 2 Suppl. 1: S38–42
Fauser AA, Duclos B, Chemaissani A, et al. Therapeutic equivalence of single oral doses of dolasetron mesilate and multiple doses of ondansetron for the prevention of emesis after moderately emetogenic chemotherapy. Eur J Cancer 1996; 32A(5): 1523–9
Bertoli L, Yeilding A, Hankins J, et al. Antiemetic dose finding study of a specific 5-hydroxytryptamine (5-HT3) receptor antagonist (MDL 73, 147EF) in patients receiving high dose cisplatin chemotherapy [abstract]. Proc Am Soc Clin Oncol 1992; 11: 395
Yeilding AL, Bertoli L, Eisenberg PD, et al. Antiemetic efficacy of two different single intravenous doses of dolasetron in patients receiving high dose cisplatin-containing chemotherapy. Am J Clin Oncol 1996; 19: 619–23
Hesketh P, Navari R, Grate T, et al. Double-blind, randomized comparison of the antiemetic efficacy of intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced emesis in patients with cancer. J Clin Oncol 1996; 14: 2242–9
Hesketh PJ, Gandara DR, Hesketh AM, et al. Dose-ranging evaluation of the antiemetic efficacy of intravenous dolasetron in patients receiving chemotherapy with doxorubicin or cyclophosphamide. Support Care Cancer 1996; 4: 141–6
Kris MG. Phase II trials of ondansetron with high-dose cisplatin. Semin Oncol 1992; 19(4) Suppl. 10: 23–7
Cooke CE, Mehra IV. Oral ondansetron for preventing nausea and vomiting. Am J Hosp Pharm 1994; 51: 762–71
Perez EA, Gandara DR. The clinical role of granisetron (Kytril) in the prevention of chemotherapy-induced emesis. Semin Oncol 1994; 21 Suppl. 5: 15–21
Bonneterre J, Hecquet B. Granisetron IV compared with ondansetron IV plus tablets in the prevention of nausea and vomiting induced by a moderately emetogenic chemotherapy regimen: a randomized cross-over study. Seventh European Conference of Clinical Oncology meeting; 1993 Nov: Jerusalem, Israel: 22–4
Jantunen IT, Muhonen TT, Kataja VV, et al. 5-HT5 receptor antagonists in the prophylaxis of acute vomiting induced by moderately emetogenic chemotherapy — a randomized study. Eur J Cancer 1993; 29A: 1669–72
Perez EA, Lembersky B, Kaywin P, et al. Intravenous granisetron vs. ondansetron in the prevention of cyclophosphamidedoxorubicin-induced emesis in breast cancer patients: a double blind crossover study [abstract]. Proc Am Soc Clin Oncol 1996; 15: 543
Perez EA, Chawla SP, Kaywin P, et al. Efficacy and safety of oral granisetron vs. IV ondansetron in prevention of moderately emetogenic chemotherapy-induced nausea and vomiting [abstract]. Proc Am Soc Clin Oncol 1997; 16: 43a
Noble A, Bremer K, Dilly SG. A double-blind, crossover comparison of granisetron and ondansetron in 5-day fractionated chemotherapy: assessment of efficacy, safety, and patient preference. Eur J Cancer 1994; 30A: 1083–8
Ruff P, Paska W, Groedhals L, et al. Ondansetron compared with granisetron in the prophylaxis of cisplatin induced acute emesis: a multicentre double-blind, randomized, parallel-group study. Oncology 1994; 51: 113–8
Mantovani A, Maccio LL, Curreli L, et al. Comparison of the effectiveness of three 5-HT3 receptor antagonists in the prophylaxis of acute vomiting induced by highly emetogenic chemotherapy (high-dose cisplatin) for the treatment of primary head and neck cancer [abstract]. Proc Am Soc Clin Oncol 1994; 13: 428
Martoni A, Angeleli B, Guaraldi M, et al. Granisetron (GRA) vs. ondansetron (OND) in the prevention of cis-platinum induced emesis: an open randomized cross-over study [abstract]. Proc Soc Am Clin Oncol 1994; 13: 431
Navari R, Gandara D, Hesketh P, et al. Comparative clinical trial of granisetron and ondansetron in the prophylaxis of cisplatininduced emesis. J Clin Oncol 1995; 13: 1242–8
Gralla RJ, Popovic W, Strupp J, et al. Can an oral antiemetic regimen be as effective as intravenous treatment against cisplatin: results of a 1054 patient randomized study of oral granisetron vs. IV ondansetron [abstract]. Proc Am Soc Clin Oncol 1997; 16: 52a
Williams PD, Cohen ML, Turk JA. Electrocardiographic effects of zatosetron and ondansetron, two 5-HT3 receptor antagonists, in anesthetized dogs. Drug Dev Res 1991; 24: 277–84
Lifsey DS, Gralla RJ, Clark RA, et al. Electrocardiographic changes with serotonin antagonist antiemetic: rate of occurrence and clinical relevance [abstract]. Proc Am Soc Clin Oncol 1993; 12: 463
Watanabe H, Hasegawa A, Shinozaki T, et al. Possible cardiac side effects of granisetron, an antiemetic agent, in patients with bone and soft-tissue sarcomas receiving cytotoxic chemotherapy. Cancer Chemother Pharmacol 1995; 35: 278–82
Ballard HS, Bottino G, Bottino J. Ondansetron and chest pain [letter]. Lancet 1992; 340: 1107
Navari RM, Kaplan HG, Gralla RJ, et al. Efficacy and safety of granisetron, a selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of nausea and vomiting induced by high-dose cisplatin. J Clin Oncol 1994; 12: 2204–10
Riviere A, Granisetron Study Group. Dose finding study of granisetron in patients receiving high-dose cisplatin chemotherapy. Br J Cancer 1994; 69 (5): 967–71
Soukop M, Granisetron Study Group. A dose-finding study of granisetron, a novel antiemetic, in patients receiving high-dose cisplatin. Supp Care Cancer 1994; 2: 177–83
Beck TM, Hesketh PJ, Madajewicz S, et al. Stratified, randomized, double-blind comparison of intravenous ondansetron administered as a multiple-dose regimen versus two singledose regimens in the prevention of cisplatin-induced nausea and vomiting. J Clin Oncol 1992; 10: 1969–75
Seynaeve C, Schuller J, Buser K, et al. Comparison of the antiemetic efficacy of ondansetron given as either a continuous infusion or a single intravenous dose, in acute cisplatin-induced emesis: a multicentre, double-blind, randomized, parallel group study. Br J Cancer 1992; 66(1): 192–7
Italian Group for Antiemetic Research. Ondansetron versus granisetron, both combined with dexamethasone, in the prevention of cisplatin-induced emesis. Ann Oncol 1995; 6: 805–10
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Perez, E.A. A Risk-Benefit Assessment of Serotonin 5-HT3 Receptor Antagonists in Antineoplastic Therapy-Induced Emesis. Drug-Safety 18, 43–56 (1998). https://doi.org/10.2165/00002018-199818010-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002018-199818010-00004