Mechanism of Action

Palonosetron is a 5-HT₃ receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors.

Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 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. It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT₃ receptors located on vagal afferents to initiate the vomiting reflex.

Pharmacodynamics

The effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc were comparable to ondansetron and dolasetron in clinical trials. In non-clinical studies palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarization and to prolong action potential duration. In clinical trials, the dose-response relationship to the QTc interval has not been fully evaluated.

Pharmacokinetics

After intravenous dosing of palonosetron in healthy subjects and cancer patients, an initial decline in plasma concentrations is followed by a slow elimination from the body. Mean maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC_0-∞ ) are generally dose-proportional over the dose range of 0.3–90 mcg/kg in healthy subjects and in cancer patients. Following single IV dose of palonosetron at 3 mcg/kg (or 0.21 mg/70 kg) to six cancer patients, mean (±SD) maximum plasma concentration was estimated to be 5.6 ± 5.5 ng/mL and mean AUC was 35.8 ± 20.9 ng•hr/mL. Following IV administration of palonosetron 0.25 mg once every other day for 3 doses in 11 cancer patients, the mean increase in plasma palonosetron concentration from Day 1 to Day 5 was 42±34%. Following IV administration of palonosetron 0.25 mg once daily for 3 days in 12 healthy subjects, the mean (±SD) increase in plasma palonosetron concentration from Day 1 to Day 3 was 110±45%.

Distribution

Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.

Metabolism

Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two primary metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron. These metabolites each have less than 1% of the 5-HT₃ receptor antagonist activity of palonosetron. In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly different between poor and extensive metabolizers of CYP2D6 substrates.

Elimination

After a single intravenous dose of 10 mcg/kg [¹⁴C]-palonosetron, approximately 80% of the dose was recovered within 144 hours in the urine with palonosetron representing approximately 40% of the administered dose. In healthy subjects, the total body clearance of palonosetron was 160 ± 35 mL/h/kg and renal clearance was 66.5± 18.2 mL/h/kg. Mean terminal elimination half-life was approximately 40 hours.

Clinical studies

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