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Are All 5-HT3 Receptor Antagonists the Same?

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Are All 5-HT3 Receptor Antagonists the Same? JN051_Jrnl_50107McNul.qxd 1/11/07 4:28 AM Page 35 35 Original Article Are All 5-HT3 Receptor Antagonists the Same? Robert McNulty, PharmD, Columbus, Ohio Key Words (CINV). In less than 2 decades, the serotonin receptor Ondansetron, granisetron, dolasetron, palonosetron, nausea, (or 5-hydroxytryptamine type 3; 5-HT3) antagonists have vomiting, chemotherapy become the cornerstone for the prevention of CINV. In the United States, four 5-HT3 antagonists are available: Abstract ondansetron, granisetron, dolasetron (a prodrug for The 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists have hydrodolasetron), and a second-generation 5-HT3 become the cornerstone for preventing and treating chemother- antagonist, palonosetron. apy-induced nausea and vomiting. Four 5-HT3 antagonists are com- mercially available in the United States, and numerous reports have The National Comprehensive Cancer Network 1 been published comparing 2 or more agents. The studies ranged from (NCCN) guidelines, American Society of Clinical randomized, double-blinded to open-label or retrospective trials; in- Oncology (ASCO) guidelines,2 and Cancer Care Ontario cluded chemotherapy-naïve and –non-naïve patients; and covered a practice guidelines3 currently describe these agents as range of doses and routes of administration with and without con- equivalent in efficacy and lack of toxicity and therapeu- comitant steroids, for preventing and treating nausea and vomiting after highly and moderately high emetogenic chemotherapy. With tically interchangeable after equipotent dosing. The lit- few exceptions, the studies uniformly show an equivalent efficacy rate erature supporting this conclusion is extensive and and side effect profile among the various agents at equivalent doses. involves more than 49 reports comparing 2 or more agents This article reviews the pharmacology of the class for insight into mi- directly in the clinical setting. The most reliable end nor differences among the agents that could possibly influence drug point for evaluating studies of antiemetic regimens is the selection for certain patients, and considers data on the absorption, half-life, metabolism, and receptor activity. Clinical trials support the incidence of emesis. Nausea tends to occur at a higher in- claim of various guidelines that the 5-HT3 receptor antagonists are cidence than vomiting, and vomiting does not usually therapeutically similar in safety and efficacy, particularly because the occur without nausea. Nausea is a symptom that can be current best practice for preventing nausea and vomiting after highly gauged only by the patient but may be indirectly quan- and moderately high emetogenic chemotherapy is a combination of tified using questionnaires and visual reporting tools. The a 5-HT3 antagonist, steroids, and aprepitant. (JNCCN 2007;5:35–43) reported perceptions of nausea correlate well with the data from the combination of emesis incidence and use In 1991, the U.S. Food and Drug Administration (FDA) of rescue medications. By defining a complete response approved ondansetron, the first commercially available as no emetic episodes and no use of rescue medications serotonin receptor antagonist for the prevention and treat- after the administration of chemotherapy, data can be ment of chemotherapy-induced nausea and vomiting measured reliably with a high degree of accuracy. Table 1 summarizes the clinical trials of 5-HT3 an- From the Arthur G. James Cancer Hospital & Richard J. Solove tagonists for CINV. Most trials compare ondansetron and Research Institute at The Ohio State University, Columbus, Ohio. granisetron, and a range of doses using both the oral and Submitted August 3, 2006; accepted for publication September 21, 2006. intravenous routes were studied. Corticosteroid steroid The author has no financial support or involvement with any use was another variable across the different trials. manufacturer of products that may be listed in the publication. Correspondence: Robert McNulty, PharmD, Arthur G. James Prophylaxis was used prior to administration of moderately Cancer Hospital & Richard J. Solove Research Institute at high and highly emetogenic regimens. Some trials also in- The Ohio State University, The Ohio State University Medical Center, 410 West 10th Avenue, Columbus, OH 43210. vestigated antiemetic therapies for preparatory regimens E-mail: [email protected] for bone marrow transplant. Single-day chemotherapy © Journal of the National Comprehensive Cancer Network | Volume 5 Number 1 | January 2007 JN051_Jrnl_50107McNul.qxd 1/11/07 4:28 AM Page 36 36 Original Article McNulty and multiday chemotherapy were studied. Study de- greater than 24 hours almost always showed less effi- signs included large trials that were randomized and cacy than the acute period. double-blinded; randomized, open label; open label; In a meta-analysis of 14 studies and 6467 patients crossover; and retrospective reports. Reports with small comparing ondansetron with granisetron in the pro- numbers of patients were included in Table 1. phylaxis of acute or delayed nausea and vomiting in Table 1 also includes the history of chemotherapy the setting of highly emetogenic or moderately eme- administration because it can substantially influence togenic chemotherapy, del Giglio et al.48 showed an ap- the results of an antiemetic trial. Populations were con- parent equivalency between the 2 agents. Likewise, sistent within studies in terms of patient gender, alco- no significant differences in adverse effects occurred, hol use, or exclusion criteria such as complaints of nausea except that patients receiving 32 mg of ondansetron or vomiting in the immediate period before chemother- intravenously experienced blurred vision and dizzi- 8 apy was administered. Table 1 lists the number of patients ness more often. The more common side effects were included in each treatment arm. headache, constipation, and diarrhea. Response rates in the table reflect complete re- Dolasetron and ondansetron were compared in a trial for moderately emetogenic agents by Fauser et al.40 sponses, that is, no emetic episodes and no use of Dolasetron, 200 mg orally, was equivalent to multiple rescue medications. If a drug was reported to be doses of ondansetron, 8 mg. Audhuy et al.42 published statistically better, then it is noted in the column a report showing intravenous granisetron and intra- after complete response rates. venous dolasetron to be equivalent in managing acute None of the randomized, double-blinded trials nausea and vomiting after treatment with highly eme- found a statistical difference in efficacy rates between togenic agents. granisetron and ondansetron. The studies with a less- Palonosetron is a second-generation 5-HT3 an- rigid design also showed equivalency between the 2 tagonist. Three randomized, placebo-controlled, non- 28 agents, with a few exceptions. Yalcin et al. reported inferiority trials compared this newer agent with an advantage to using granisetron, 3 mg intravenously, first-generation 5-HT3 antagonists. Gralla et al.45 com- over ondansetron, 8 mg intravenously, for moderately pared 2 dose levels of palonosetron with a single dose emetogenic chemotherapy. Study size was small at 18 of ondansetron, 32 mg intravenously, in the manage- or 19 patients per study arm. In a retrospective review ment of nausea and vomiting after treatment with of antiemetic therapy, Dempsey et al.38 found that moderately emetogenic chemotherapy in chemother- ondansetron, 8 mg intravenously, was inferior to apy-naive and –non-naive patients not treated with granisetron, 10 mcg/kg per dose. The study arms dif- steroids. Palonosetron, 0.25 mg intravenously, was sta- fered in that the ondansetron group was exposed to ra- tistically better than ondansetron in both complete diation more often, and corticosteroid use was less control of acute nausea and vomiting and delaying frequent in the ondansetron arm. Equivalent efficacy nausea and vomiting. was also mostly reported in the setting of bone mar- Palonosetron, 0.75 mg, was found to have no sta- row transplants. The trial by Spitzer et al.16 showed a tistical difference from ondansetron. Aapro et al.46 numerical superiority of granisetron over ondansetron, studied palonosetron, 0.25 mg intravenously and 0.75 but the study arms were too small for statistical analy- mg intravenously, against ondansetron, 32 mg intra- sis. Lacerda et al.20 observed that ondansetron, 24 mg/d, venously, in both chemotherapy-naive and –non-naive was superior to granisetron, but that 16 mg/d of on- patients with and without steroids undergoing highly dansetron was equivalent. Only 16 and 24 patients emetogenic regimens. The 2 drugs showed no statis- were included in the study arms for ondansetron, 16 tical difference either during the acute or the delayed mg and 24 mg, respectively. phases. 47 For delayed emesis, efficacy was also similar among Eisenberg et al. compared dolasetron, 100 mg in- the first-generation 5-HT3 antagonists. A single dose travenously, with palonosetron, 0.25 mg intravenously of granisetron was reported by Stewart et al.11 to be and 0.75 mg intravenously, after moderately emeto- genic chemotherapy in chemotherapy-naive and less effective against delayed nausea than a multi-day –non-naive patients. A small percentage of patients regimen of ondansetron. An argument can be made that these were not equivalent doses. The period text continued on p. 5 © Journal of the National Comprehensive Cancer Network | Volume 5 Number 1 | January 2007 JN051_Jrnl_50107McNul.qxd
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