Aloxi Palonosetron A New Anti Emetic Agent Biology Essay

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Nausea and vomiting is the most common adverse effect of chemotherapy 1. It is also regarded by patients as one of the most unpleasant and concerning adverse effects of chemotherapy, and is a major reason for patients abandoning chemotherapy treatment 2,3. The incidence and severity of chemotherapy induced nausea and vomiting (CINV) is dependent on the type of chemotherapy and patient specific risk factors. Patient specific risk factors include female gender, age 50 years, history of low alcohol intake, history of previous chemotherapy-induced emesis, history of motion sickness, and history of emesis during a past pregnancy 4. CINV is categorized into 4 stages based on the timing of the nausea and vomiting from chemotherapy: acute (24 hours post treatment; most common), delayed (1-7 days post treatment), anticipatory (before chemotherapy), and breakthrough (CINV despite preventative therapy) CINV 4. CINV involves the activation of the chemoreceptor trigger zone in the medulla, cerebral cortex, and gastrointestinal tract by chemotherapeutic agents, that results in the coordinated secretory and muscle contractions that drives emesis 1. Serotonin receptor subtype 3 (5-HT3) in the CNS and GI tract are one of the receptors involved in this process, and is the target of antiemetic agents that belong in the 5-HT3 receptor antagonist class 4.

Although first generation 5-HT3 receptor antagonists (ie. granisetron, ondasetron, dolasetron) are equally effective in preventing acute CINV, the same cannot be said about their role in delayed CINV 2. In fact, a systematic review did not find sufficient evidence for the use of first generation 5-HT3 receptor antagonists to be used beyond 24 hours after chemotherapy for the prevention of delayed CINV 5.

Palonosetron (Aloxi)

Palonosetron, sold under the brand name Aloxi, was recently approved by Health Canada for the prevention of chemotherapy induced acute and delayed nausea and vomiting 8. The Notice of Compliance for Aloxi was issued on March 14, 2012.


Palonosetron is a second generation 5-HT3 receptor antagonist with a higher binding affinity, potency, and longer half life (~40 hours vs. 9 hours) than all first generation agents 6. The binding affinity of Palonosetron is at least 30 fold higher than first generation 5-HT3 receptor antagonists, which may be explained by its allosteric binding and positive cooperativity versus simple bimolecular binding for the older agents 2,7. Molecular studies has further shown that palonosetron triggers 5-HT3 receptor internalization, which prolongs its inhibitory effect on the receptor 7.


Oral bioavailability of palonosetron is about 97%, and is not affected by food consumption8. It has a volume of distribution of 8.3 L/kg, and is 62% protein bound. Palonosetron is metabolized by CYP2D6, CYP3A4, and CYP1A2. The route of elimination is primary in the urine, with 42% as unchanged drug.


There is no dosage adjustment required for palonosetron for renally and hepatically impaired patients 8,9. It’s effects on pregnancy is largely unknown, but It is not recommended in lactation due to the lack of supporting data in that patient population. Animal studies did not find fetal risk but the effects on pregnant women are largely unknown. Palonosetron is categorized under pregnancy risk factor B, and should be used in pregnancy only when needed.

Health Canada Indications and Supporting Evidence

IV Palonosetron

The prevention of acute and delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy 8.

In a combined analysis of two phase III randomized controlled trails with 1132 total patients, single dose IV palonosetron 0.25mg and 0.75mg administered 30 minutes before chemotherapy was demonstrated to be non-inferior to single dose IV ondansetron 32mg or IV dolasetron 100mg in the prevention of acute CINV. Palonosetron 0.25mg (but not 0.75mg) was also superior over the comparator groups in the prevention of delayed CINV.

The prevention of acute nausea and vomiting associated with highly emetogenic cancer chemotherapy 8.

In a phase III randomized controlled trial with 667 patients, single dose IV palonosetron 0.25mg and 0.75 mg administered 30 minutes before chemotherapy with corticosteroids was non-inferior to IV ondansetron 32mg with corticosteroids for the prevention of acute CINV. However, the study did not find superiority for palonosetron for delayed CINV. The non-inferiority of palonosetron demonstrated here requires the co-administration of a prophylactic corticosteroid.

Oral Palonosetron

The prevention of acute nausea and vomiting associated with moderately emetogenic cancer chemotherapy 8.

In a randomized control study with 635 patients, single dose oral palonosetron 0.25mg, 0.5mg, or 0.75mg 1 hour before chemotherapy was shown to be non-inferior to single dose IV palonosetron 0.25mg 30 minutes before chemotherapy for the prevention of acute CINV. Efficacy was further improved when either oral or IV palonosetron was used in conjunction with corticosteroids.

Systematic review and meta-analysis 3

A recent systematic review and meta-analysis of randomized controlled trails investigated the efficacy of a single IV dose of palonosetron 0.25mg compared to other 5-HT3 receptor antagonists (ondansetron, granisetron, and dolasetron) in patients receiving moderately to highly emetogenic chemotherapy. Palonosetron was found to be significantly more effective in preventing acute and delayed CINV than first generation agents.


The safety and tolerability of palonosetron did not differ significantly from ondansetron or dolasetron. The most common adverse effects include headaches (3-9%) and constipation (2-5%) 2,9. Palonoestron appears to be the safest of the 5-HT3 receptor antagonists to use if risk of QT prolongation is a concern, although there is still a small risk so use should be with caution 10.


Palonosetron is not on the Ontario Drug Benefit (ODB) formulary unlike the other 5-HT3 receptor antagonists which are limited use drugs covered under the ODB. A single dose of palonosetron for CINV costs about $70 whereas ondansetron costs about $16-32 10,11.


Palenosetron is available in intravenous (0.05 mg/mL solution) and oral formulations (0.5mg capsule) 8.

Role in Clinical Practice

The 2011 antiemetics guidelines from the American Society of Clinical Oncology (ASCO) recommended Palonosetron for the prevention of CINV from moderately emetogenic chemotherapy agents 2. In the moderate emetic risk category, a two drug combination of palonosetron (day 1: 0.25mg IV; 0.5mg oral), and dexamethasone (days 1-3: 8mg IV/PO) was recommended. Palonosetron was also a therapeutic option in the day one regimen for the high emetic risk category: NK1 receptor antagonist (day 1-3 for aprepitant; day 1 only for fosaprepitant), a 5-HT3 receptor antagonist (day 1), and dexamethasone (days 1-3 or 1-4).