5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are used to treat nausea and vomiting and in the prevention of chemotherapy-induced, radiation-induced, and postoperative nausea and vomiting. Most of the 5-HT3 receptor antagonists (i.e., ondansetron, tropisetron, dolasetron, palonosetron, and ramosetron) are metabolized by CYP2D6, but the extent of CYP2D6 involvement varies. CYP2D6 genetic variation can influence the metabolism of these medications, particularly ondansetron and tropisetron, thereby affecting drug efficacy. This guideline is an update to the 2016 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and use of ondansetron and tropisetron and includes updated information on CYP2D6 genetic testing and evidence tables. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for 5-HT3 receptor antagonists based on CYP2D6 genotype, particularly where genetic variation is associated with reduced drug efficacy (updates at https://www.clinpgx.org/guideline/PA166251457).

Little information is available on the use of dolasetron during breastfeeding. Until more data become available, dolasetron should be used with caution during breastfeeding. An alternate drug may be preferred.

5-hydroxytryptamine-3 (5-HT3) receptor antagonists including ondansetron, tropisetron, dolasetron, palonosetron, granisetron, and ramosetron are commonly used to prevent and treat nausea and vomiting. Most of these medications are at least partially metabolized via the highly polymorphic CYP2D6 enzyme, resulting in variations of metabolism among individuals. Current (2017) international prescribing guidelines for ondansetron/tropisetron use according to genotype provide recommendations for CYP2D6 ultrarapid metabolizers but not intermediate or poor metabolizers. However, multiple studies have been conducted since this guideline was published. This review evaluated all available evidence of an association between CYP2D6 genotype and 5-HT3 receptor antagonist outcomes, including in patients who are CYP2D6 intermediate/poor metabolizers and pediatric-specific studies. In this review, we confirm that CYP2D6 genotype impacts ondansetron response in a postoperative nausea and vomiting setting, which was supported by a meta-analysis. We also highlight the heterogeneity and limitations of included studies as well as provide future directions for pharmacogenomics research.

The ICH E14/S7B Q&As highlighted the need for best practices concerning the design, execution, analysis, interpretation, and reporting of the in vivo non-rodent QT assay as a component of the integrated risk assessment to potentially support a TQT waiver or substitute. We conducted a dog telemetry study to assess the effects on QTc of six reference compounds (five positive and one negative) previously evaluated by Darpo et al. (2015) in humans. The sensitivity of the assay to detect QTc increases was determined, and exposure-response analysis was performed, as done in clinical practice. By-timepoint analysis showed QTc prolongation induced by moxifloxacin, dofetilide, dolasetron, ondansetron, and quinine within human relevant plasma exposures ranges. Moreover, a hysteresis was observed for quinine. As expected, levocetirizine showed no statistically significant effect on QTc across a range of exposure, well exceeding the therapeutic Cmax. Power analyses confirmed the study ability to detect statistically significant QTc changes of less than 10 milliseconds with 80% probability, even with a sample size as low as n = 4 animals. Finally, concentration-QTc modeling enabled to predict the minimal plasma concentration needed to detect a 10 milliseconds QTc prolongation, including for quinine. The comparison with clinical available data supported the relevance of dogs under these experimental conditions as a robust translational predictor of drug-induced QTc prolongation in humans as a key pillar of the integrated risk assessment.

Clinical trials of new drugs often face a high failure rate of approximately 45 percent due to safety and toxicity concerns. Repurposing drugs with well-established safety profiles becomes crucial in addressing this challenge. Colon cancer ranks as the third most prevalent cancer and the second leading cause of cancer related mortality worldwide. This study focuses on the RNA-binding protein pumilio1 (PUM1), a member of the PUF family involved in post-transcriptional gene expression regulation. By utilizing molecular docking techniques and FDA-approved drugs, potential inhibitors against PUM1 were identified. Notably, dolasetron and ketoprofen demonstrated promising results, exhibiting strong binding affinity, hydrophobic interactions, and favorable chemical reactivity according to Conceptual-DFT calculations. Both compounds effectively reduced cell viability, with IC50 values of 150 µM and 175 µM, respectively and shows long term inhibitory effects as seen by reduced in number of colonies. Moreover, they exhibited inhibitory effects on colon cancer stem cells, as indicated by reduced colonospheroid size and numbers. Apoptosis is induced by these compounds and has triggered activation of executioner caspase 3/7 in HCT116 cells which is evident through a caspase 3/7 assay and AO/EB staining, while the non-toxic effect of these compounds was evident from viability against non-cancerous cell line and hemolysis assay. Additionally, the treatment group showed a significant decrease in PUM1 and cancer stem cell markers expression compared to the control group. In conclusion, this study highlights the potential of targeting PUM1 as a novel approach to colon cancer treatment. Dolasetron and ketoprofen demonstrate promise as effective anti-cancer and anti-cancer stem cell drugs, inducing apoptosis in colon cancer cells through inhibition of PUM1.

An important group of antiemetic drugs used in the treatment of nausea and vomiting after chemotherapy containing an indole moiety in their structures, working as 5- hydroxytryptamine type 3 serotonin receptor antagonist (5-HT3). This study focuses on compounds bearing an indole core that present a 5-HT3 receptor antagonist activity, which have been successfully used as antiemetic drugs for reducing chemotherapy adverse secondary effects during cancer treatment. Their synthesis, biological activities, and some outstanding characteristics are discussed, providing a general outlook towards the development of more efficient antiemetic drugs.

The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that ondansetron, a 5-HT3 antagonist drug used to prevent nausea and vomiting, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test the ability of five 5-HT3 antagonist drugs to inhibit the OCT2 and MATE1 transporters. The transport of the OCT2/MATE1 probe substrate ASP[+] was assessed using two models: (1) HEK293 kidney cells overexpressing human OCT2 or MATE1, and (2) MDCK cells transfected with human OCT2 and MATE1. In HEK293 cells, the inhibition of ASP[+] uptake by OCT2 listed in order of potency was palonosetron (IC50: 2.6 μM) > ondansetron > granisetron > tropisetron > dolasetron (IC50: 85.4 μM) and the inhibition of ASP[+] uptake by MATE1 in order of potency was ondansetron (IC50: 0.1 μM) > palonosetron = tropisetron > granisetron > dolasetron (IC50: 27.4 μM). Ondansetron (0.5-20 μM) inhibited the basolateral-to-apical transcellular transport of ASP[+] up to 64%. Higher concentrations (10 and 20 μM) of palonosetron, tropisetron, and dolasetron similarly reduced the transcellular transport of ASP[+]. In double-transfected OCT2-MATE1 MDCK cells, ondansetron at concentrations of 0.5 and 2.5 μM caused significant intracellular accumulation of ASP[+]. Taken together, these data suggest that 5-HT3 antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.

Chemotherapy-induced nausea and vomiting (CINV) is 1 of the most debilitating side effects of cancer therapy, affecting up to 80% of chemotherapy patients.1 Chemotherapy drugs are classified according to the associated risk of causing CINV: minimal (less than 10%), low (10% to 30%), moderate (30% to 90%), and high (greater than 90%).2 High emetogenic chemotherapy (HEC) drugs include a high dose of cisplatin, a high dose of cyclophosphamide (1,500 mg/m2 or more), and a combination of anthracycline and cyclophosphamide (AC).2 Moderate emetogenic chemotherapy (MEC) regimens are more variable including carboplatin, oxaliplatin, doxorubicin, and cyclophosphamide.2 CINV symptoms can manifest at various time points after chemotherapy. There are 3 distinct types of CINV: Acute CINV occurs within 24 hours after administration of chemotherapy, with acute vomiting and nausea, and is primarily mediated by the 5-hydroxytryptamine-3 (5-HT3) receptor antagonist. Delayed CINV occurs from 24 hours to 5 days after chemotherapy and is predominantly mediated by the neurokinin 1 (NK1) receptor antagonists. Anticipatory CINV occurs before chemotherapy treatment as a conditioned response because of the development of significant CINV from the previous chemotherapy cycles, mediated by both physiologic and psychological mechanisms.2,3. The management of CINV has been facilitated from the development of various antiemetic agents with different mechanisms of action. Three most commonly used medications for antiemetic prophylaxis are 5-HT3 receptor antagonists (5-HT3 RA), NK1 RA, and corticosteroids, usually dexamethasone (DEX).3,4 Other antiemetic agent such as olanzapine, an atypical antipsychotic, has been used for acute and delayed CINV.3,4 These antiemetic agents are used in specific combinations depending on the emetogenicity of the chemotherapy regimen given to different population (i.e., adults or children).3,4 Currently available 5-HT3 RAs for CIVN include ondansetron, granisetron, dolasetron, and palonosetron.3,4 The NK1 RA include aprepitant, fosaprepitant, and rolapitant.3,4 On March 14, 2012, Health Canada issued a Notice of Compliance for the IV and oral formulation of palonosetron. IV palonosetron is indicated in adults for “the prevention of acute and delayed nausea and vomiting associated with MEC and the prevention of acute nausea and vomiting associated with HEC, including high dose cisplatin. Oral palonosetron is indicated in adults for the prevention of acute nausea and vomiting associated with MEC”.5 Palonosetron is a long-lasting, second-generation agent, with higher affinity and binding capacity to 5-HT3 receptor, and thus has a longer half-life of 40 hours compared to first-generation 5-HT3 RAs, ondansetron, granisetron, dolasetron, and with a half-life of 3 to 9 hours.6 Due to its long half-life, palonosetron has been suggested to produce best treatment responses in both acute and delayed CINV of varying emetogenicity.6 On September 28, 2017, Health Canada issued a Notice of Compliance for netupitant/palonosetron (NEPA) — a combination of a highly selective NK1 RA netupitant (300 mg) and palonosetron (0.5 mg) — in combination with DEX, for once-per-cycle treatment in adult patients for the “prevention of acute and delayed nausea and vomiting associated with HEC and prevention of acute nausea and vomiting associated with MEC therapy that is uncontrolled by a 5-HT3 RA.”7,8 Over the past decades, the development of new antiemetic drugs has progressed and shown promising results in the prevention of CINV. Particularly, the appearance of second-generation of 5-HT3 receptor palonosetron and its combination with netupitant in NEPA has urged a literature review on the clinical effectiveness and cost-effectiveness of these drugs relative to other 5-HT3 RAs. Both dosage forms of palonosetron (IV and oral) were reviewed by the CADTH Common Drug Review in 2012.9–12 The combination product palonosetron-netupitant (Akynzeo) was reviewed in 2017.13–15 Since then, new evidence and guidelines have emerged on the use of palonosetron as monotherapy or in combination with netupitant to treat adults and children with CINV. The aim of this report is to review the clinical effectiveness and cost-effectiveness of palonosetron for the prevention of CINV in patients receiving HEC or MEC. The report also summarizes the evidence-based guidelines regarding the use of palonosetron for the prevention CINV in patients receiving HEC or MEC.

Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting. These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryoelectron microscopy structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.

Review the clinical evidence of tropisetron or palonosetron, an old- and new-generation serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptor antagonist (RA), respectively, for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with cancer, and evaluate any difference in efficacy trends. A literature search of the EMBASE and PubMed databases was performed to identify publications of intravenous (IV) tropisetron (generic forms or Navoban®) for the treatment of CINV in patients with various cancers. Data from the pivotal clinical studies evaluating the IV formulation of Aloxi® (palonosetron HCl) were also considered. The effectiveness and safety of each antiemetic was summarized. Sixteen papers for tropisetron fulfilled the inclusion criteria and were extracted for full analysis; publications from six pivotal palonosetron clinical trials were considered. No direct data comparisons could be made between the two drugs, due to the varying definitions of efficacy endpoints between studies. For tropisetron, the rates of no emesis were lower in patients receiving highly emetogenic chemotherapy (HEC) versus moderately emetogenic chemotherapy (MEC). For palonosetron, the rates of complete response (no emesis, no rescue medication) were comparable in the MEC and HEC settings, demonstrating the effectiveness of this agent in patients receiving HEC. Both antiemetics offered some protection against nausea, although lower rates of no nausea were achieved compared with rates of no emesis. Two trials that evaluated the efficacy of palonosetron and tropisetron within the same study reported that palonosetron was more effective than tropisetron in controlling delayed vomiting in the HEC and MEC settings, with significantly higher rates of no emesis observed (P≤0.01). Palonosetron was non-inferior or more efficacious in controlling CINV compared with other older 5-HT3RAs, such as dolasetron, ondansetron, and granisetron. Conversely, tropisetron was no more efficacious than ondansetron or granisetron. Both tropisetron and palonosetron were generally well tolerated, with adverse event profiles consistent with drugs of this class (e.g., headache, constipation, and diarrhea). These data suggest that palonosetron is a highly selective prophylactic agent that may have an improved therapeutic profile compared with tropisetron, and is a feasible treatment option for controlling CINV in patients with cancer.