Brand Name: Aloxi®

Generic Name: palonosetron, now available as oral capsules           

Manufacturer: Catalent Pharma Solutions; distributed by Eisai Inc.

Drug Class: Antiemetic/ Serotonin receptor antagonist (5-HT3)

Uses:   Acute chemotherapy-induced nausea/vomiting: prophylaxis

Mechanism of Action: palonosetron is a serotonin receptor antagonist with a strong affinity for binding 5-HT3 with minimal to no affinity for other receptor types. The 5-HT3 receptors are present in the vagal nerve terminals and in the chemoreceptor trigger zone (CTZ). The cytotoxic agents induce emesis by releasing serontonin from the enterochromaffin cells in the small intestine which activates the 5-HT3 receptors in the vagal afferents. Palonosetron blocks this activation which prevents signal transmission to the CTZ thereby reducing the incidence of nausea and vomiting.

Pharmacokinetics:

Metabolism: palonosetron hydrochloride is metabolized primarily in the liver with approximately 50% metabolized by cytochrome P450, including CYP2D6, CYP3A4, and CYP1A2. Two metabolites are formed that have less than 1% of the activity of the parent compound.

Elimination: approximately 85-93% of an oral dose of palonosetron is excreted in the urine, with about 40% being unchanged.

Efficacy:

Aapro MS, Grunberg SM, Manikhas GM, Olivares G, Suarex T, Tjulandin SA, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vaomiting following highly emetogenic chemotherapy. Annals of Oncology. 2006;17:1441-1449.

Study Design: This study was a randomized phase III trial. It was a multinational, double-blind/double-dummy, stratified, parallel, active compared study.

Description of study: The study compared IV palonosetron with ondansetron for prevention of acute and delayed chemotherapy-induced nausea and vomiting. The patients were randomized to receive a single IV dose of palonosetron 0.25 mg, palonosetron 0.75 mg, or ondansetron 32 mg prior to receiving highly emetogenic chemotherapy (HEC). The primary endpoint was the proportion of patients with complete response during the 24 hours post-chemotherapy. It was found that palonosetron 0.25 mg and 0.75 mg were at least as effective as ondansetron in preventing acute chemotherapy induced nausea and vomiting (CINV).  The complete response rates were 59.2%, 65.5%, and 57% for the palonosetron 0.25mg, 0.75 mg and the ondansetron 32 mg groups respectively. All treatments were well tolerated.

Limitations: Patients who had received chemotherapy before were not excluded from the study and is a potential source of bias because some of those patients may have not had any nausea the first time and may not be susceptible to that side effect. Another limitation is that chemotherapy regimens are not standardized and the heterogeneity of the regimens can lead to different side effect profiles.

Conclusion: The single dose of palonosetron was at least as effective as ondansetron. The effectiveness of palonosetron was significantly increased compared to ondansetron through the 5 days post-chemotherapy.

Yu Z, Wenchao L, Wang L, Liang H, Huang Y, Si X, et al. The efficacy and safety of palonosetron compared with granisetron in preventing highly emetogenic chemotherapy-induced vomiting in the Chinese cancer patients: a phase II, multicenter, randomized, double-blind, parallel, comparative clinical trial. Support Care Cancer. 2008.

Study Design: Phase II, multicenter, randomized, double-blind, parallel, comparative trial.

Description of study: Conducted to evaluate the efficacy and safety of palonosetron in preventing chemotherapy induced vomiting among Chinese cancer patients. Palonosetron was compared against granisetron. The study used a single dose of 0.25 mg of palonosetron versus a 3 mg dose of granisetron. The primary endpoint was the complete response rate for acute chemotherapy induced vomiting. The complete response rates were 82.69% for palonosetron and 72.12% for granisetron, which demonstrating the non-inferiority of palonosetron when compared to granisetron. Adverse events were mild to moderate, with low rates in both groups.

Limitations: Phase II trial, only a Chinese cancer patient population, and the fact that this study was a non-inferiority trial are all limitations.

Conclusion: A single dose of palonosetron is not inferior to a single dose of granisetron in preventing Chemo-induced vomiting and palonosetron has an acceptable safety profile in the Chinese Population.

Rojas C, Stathis M, Thomas A, Massuda E, Alt J, Zhang J, et al. Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor. Anesthesia and Analgesia. 2008;107(2):469-478.

Study Design: Used radioligand binding assays, plasmid preparation, and cell transfections to compare the molecular interactions of palonosetron with other 5-HT3 receptor antagonists.

Description of study: Determining the clinical effectiveness of palonosetron versus other 5-HT3 receptor antagonists. Receptor site saturation binding experiments were done with palonosetron, granisetron, and ondansetron to obtain corresponding Scatchard analyses and Hill coefficients. The long term effect of the three antagonists on receptor function as measured by calcium influx was compared. These tests showed that palonosetron was an allosteric antagonist whereas granisetron and ondansetron were competitive antagonists. Substantial inhibition of calcium-ion influx was observed in cells that had been incubated with palonosetron and these inhibition was not seen with granisetron or ondansetron.

Limitations: This study was not a clinical trial and the invitro results may not be consistent with invivo results.

Conclusion: Palonosetron interacts with the serotonin receptors differently than other 5-HT3 receptor antagonists. This difference allows a receptor alteration or internalization resulting in a long-lived inhibition.  Palonosetron exhibits allosteric binding and the prolonged inhibition of serotonin induced calcium ion influx indicates that the effects last longer. 

Contraindications: palonosetron is contraindicated in patients with a hypersensitivity to palonosetron or any of the drug’s components.

Precautions: use is cautioned in patients who have cardiac disease, dehydration, hypocalcemia, hypokalemia, hypomagnesemia, hyperkalemia, patients taking anti-arrhythmic or other drugs that may lead to QT prolongation or electrolyte imbalance. The QT prolongation has been removed from the warnings on the package but may still be a caution for this medication.

Adverse Effects: adverse effects reported in 1% or more of patients receiving palonosetron include headache, constipation, diarrhea, dizziness, nonsustained tachycardia, weakness, hyperkalemia, and anxiety

Drug Interactions: There is low potential for clinically significant drug interactions with palonosetron. Any medication that prolongs QT interval may interact with palonosetron. 

Dosing/Administration: 0.5 mg PO as a single dose approximately 60 minutes prior to chemotherapy.

Use in special circumstances: Pregnancy category B, little data on use while breast-feeding, manufacturer warns against it. No dosage adjustment necessary in renal or hepatic impairment.

Conclusion: The new oral dosage form of palonosetron hydrochloride is a good option for prevention of chemo-induced nausea and vomiting. Only one dose is given about 30 minutes prior to the chemo and the oral dosage form gives patients more flexibility because they could take it at home before they leave for the hospital and not have to spend an extra half hour in the hospital/clinic where they receive their therapy.

Palonosetron has been shown to be effective and works slightly differently than other medications in the class. The unique mechanism may eventually put palonosetron as the front-runner for 5-HT3 receptor antagonists. More studies need to be done comparing the oral formulation with the mainstay IV formulations

Recommended References:

1. Clinical Pharmacology – palonosetron
2. Micromedex – palonosetron
3. Lexi-Comp online – AHFS DI – palonosetron
4. Aloxi product information from manufacturer

Prepared by: Kari E. McDonald, Pharm.D. Candidate