General Information

Aloxi (palonosetron) is an injectable anti-vomiting and anti-nausea agent taken just chemotherapy treatments. Palonosetron belongs to a relatively new, but well-known, class of anti-emetics, the 5-HT3 receptor antagonists.

Aloxi is indicated for the prevention of acute or delayed nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy.

The recommended dosage of Aloxi is 0.25 mg administered as a single dose approximately 30 minutes before the start of chemotherapy. In Europe, the Palonosetron trademark is licensed under the name Onicit. It will be marketed in Italy by Italfarmaco, a privately owned pharmaceutical company.

Clinical Results

FDA approval of Aloxi is based on three phase III clinical trials and one phase II study. Complete response rates, defined as no emetic episodes and no rescue medication, and other efficacy parameters were assessed through a total of 120 hours of treatment of chemotherapy and palonosetron injection.

Two-phase III trials tested the efficacy of Aloxi against moderately emetogenic chemotherapy treatment. The multicenter, randomized, double blind studies (called 99-03 and 99-04) enrolled 1,132 subjects and designed to compare the efficacy and safety profile of palonosetron with that of a comparator agent for prevention of CINV. Subjects in the 99-03 study were randomized to receive single intravenous doses of 0.25 mg palonosetron, 0.75 mg palonosetron, or 32 mg ondansetron 30 minutes prior to moderately-emetogenic chemotherapy. In study 99-04, subjects in the comparator arm received 100 mg dolasetron as the comparator agent.

Results showed that the complete response rate for subjects in the 0.25 mg palonosetron arm was significantly greater than the complete response rate among patients who received 32 mg ondansetron. During the first 24 hours following chemotherapy, also called the acute phase, 81.0% of the subjects treated with a single intravenous 0.25 mg dose of palonosetron achieved a complete response, compared to 68.6% of patients treated with 32 mg ondansetron. During the delayed phase, 74.1% of subjects treated with 0.25 mg palonosetron had a complete response compared to 55.1% of patients in the 32 mg ondansetron study arm. Results from study 99-03 were presented in an ASCO Integrated Education Session entitled "Pathogenesis-Based Treatment of Mucositis and Nausea and Vomiting". Results from the 99-04 trial were reported in June 2002 at the Multinational Association of Supportive Care in Cancer (MASCC) International Symposium.

A third double-blind, phase 3 trial (99-05) enrolled 667 subjects and compared single-dose IV ALOXI with single-dose IV ondansetron (study 3) given 30 minutes prior to highly emetogenic chemotherapy including cisplatin ¡Ý 60 mg/m2, cyclophosphamide > 1500 mg/m2, and dacarbazine. Results showed that during the delayed phase 45.3% of subjects treated, with 0.25 mg palonosetron had a complete response compared to 38.9% of subjects in the 32 mg ondansetron trial arm. Additionally, 42.0% of the subjects given dexamethasone prior to chemotherapy and treated with a single intravenous 0.25 mg dose of palonosetron achieved a complete response during the delayed phase, compared to 28.6% of subjects treated with 32 mg ondansetron. Data showed that the median time to first emetic episode for subjects treated with palonosetron was more than 120 hours, compared to 42.7 hours for subjects treated with 32 mg ondansetron.

A double-blind, dose-ranging phase 2 study evaluated the efficacy of single-dose IV palonosetron from 0.3 to 90 µg/kg (equivalent to < 0.1 mg to 6 mg fixed dose) in 161 chemotherapy-naïve adult cancer patients receiving highly-emetogenic chemotherapy (either cisplatin ¡Ý 70 mg/m2 or cyclophosphamide > 1100 mg/m2). Concomitant corticosteroids were not administered prophylactically. Results indicated that 0.25 mg is the lowest effective dose in preventing acute nausea and vomiting induced by highly emetogenic chemotherapy.

Mechanism of Action

Palonosetron is a selective serotonin subtype 3 (5-HT3) receptor antagonist with a strong binding affinity. 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. Cancer chemotherapy is associated with nausea and vomiting when serotonin is released from the enterochromaffin cells of the small intestine activates 5-HT3 receptors located on vagal afferents and activates the vomiting reflex. Palonosetron may also block ion channels involved in ventricular polarization may prolong action potential duration. The effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc were comparable to ondansetron and dolasetron in clinical trials.

Literature References

Bonhaus DW, Stefanich E, Loury DN, Hsu SAO, Eglen RM and Wong EHF Allosteric interactions among agonists and antagonists at 5-hydrotryptamine-3 receptors. J Neurochem 65(1):104-110, 1995.

Chelly J, Melson T, Pollock J, et al. Oral RS-25259 prevents postoperative nausea and vomiting following laparoscopic surgery. Anesthesiol 85(Suppl. 21): abstract no. 3A, 1996. Kowalczyk BA and Dyson NH

Clark RD, Miller AB, Berger J, et al. 2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists. J Med Chem, 36(18):2645-2657, 1993.

DiVall MV and Cersosimo RJ Palonosetron. A novel 5-HT3 receptor antagonist for chemotherapy-associated nausea and vomiting. Formulary, 38:414-430, 2003.