Palonosetron

Palonosetron is a second-generation serotonin 5-HT₃ receptor antagonist, with a distinct pharmacological profile that differs from first-generation 5-HT₃ receptor antagonists. Intravenous palonosetron is widely indicated for the prevention of chemotherapy-induced nausea and vomiting (CINV) in the acute and delayed phases following moderately emetogenic chemotherapy (MEC) and the prevention of CINV in the acute phase following highly emetogenic chemotherapy (HEC). In the US, oral palonosetron is approved for the prevention of CINV in the acute phase following MEC (although this formulation is not currently available), and intravenous palonosetron is indicated for the prevention of postoperative nausea and vomiting (PONV) in the first 24 hours following surgery. All indications are currently limited to adult patients.

Intravenous palonosetron was noninferior to intravenous ondansetron (with statistically greater efficacy than ondansetron) or dolasetron in preventing CINV following MEC, or to intravenous ondansetron or granisetron in preventing CINV following HEC, in the acute phase. Statistically greater efficacy was seen with intravenous palonosetron than ondansetron or dolasetron in preventing CINV following MEC in the delayed phase. Oral palonosetron was noninferior to intravenous palonosetron in preventing CINV in the acute phase in patients receiving MEC. Intravenous palonosetron was superior to placebo in preventing PONV in the first 24 hours following surgery. Palonosetron was generally well tolerated in clinical trials. Intravenous palonosetron is a valuable option in the prevention of acute- and delayed-phase CINV in adult patients receiving MEC, and of acute-phase CINV in patients receiving HEC. Oral palonosetron is likely to be a useful addition to oral formulations of other 5-HT₃ receptor antagonists in preventing CINV in patients receiving MEC. Intravenous palonosetron is a useful alternative to currently recommended agents in PONV prevention.

Although all 5-HT₃ receptor antagonists prevent nausea and vomiting by selective inhibition of 5-HT₃ receptors, palonosetron is structurally different to, and has a higher affinity for the 5-HT₃ receptor than, the other 5-HT₃ receptor antagonists; it is the only allosteric antagonist and has a long duration of action. Palonosetron has no clinically relevant effects on the cardiovascular system, including prolongation of the corrected QT interval.

The pharmacokinetic profile of intravenous palonosetron is generally similar between patients receiving chemotherapy and those undergoing surgery. Oral palonosetron has a bioavailability of 97%. Palonosetron is extensively distributed and is ≈62% bound to plasma proteins. Cytochrome P450 (CYP) accounts for ≈50% of palonosetron metabolism, mainly by CYP2D6, CYP3A4 and CYP1A2; the major metabolites have minimal antagonistic activity (<1%) at the 5-HT₃ receptor. Palonosetron has a long terminal elimination half-life (mean ≈40 hours) and is excreted mainly through the urinary route. Dose adjustment of palonosetron is not needed on the basis of age, sex, race, renal or hepatic impairment, concurrent medication or clinical chemistry.

In randomized, double-blind, multicentre trials, intravenous palonosetron was noninferior to intravenous ondansetron or dolasetron in preventing CINV in the acute phase in patients receiving MEC, with statistically better efficacy than ondansetron or dolasetron in subsequent superiority analyses in the acute and delayed phases. Intravenous palonosetron was noninferior to intravenous ondansetron or granisetron in preventing CINV in the acute phase following HEC. Intravenous palonosetron in combination with dexamethasone with or without aprepitant was an effective CINV prophylactic regimen. Oral palonosetron was noninferior to intravenous palonosetron in preventing CINV in the acute phase in patients receiving MEC in another trial. Intravenous palonosetron was generally associated with better health-related quality-of-life outcomes compared with intravenous ondansetron or dolasetron in patients receiving MEC, or with intravenous ondansetron in patients receiving HEC. Superior efficacy of intravenous palonosetron over placebo in preventing PONV in the 0–24 hour time period was established in two other trials.

Cost analyses modelled on two European hospital perspectives in patients receiving MEC or HEC suggested pharmacoeconomic benefits associated with the use of palonosetron compared with that of ondansetron or first-generation 5-HT₃ receptor antagonists in the management of CINV. A large US observational study (in patients receiving various chemotherapy regimens) reported a more favourable financial impact following the use of palonosetron compared with that of ondansetron for preventing CINV.

In clinical trials, the intravenous and oral formulations of palonosetron were generally well tolerated in patients receiving chemotherapy, and intravenous palonosetron was generally well tolerated in surgical patients. The incidence of reported adverse events was low (all <10%), and the majority of these were of mild or moderate severity; no or few study withdrawals as a result of adverse events were attributed to study medication. Headache and constipation were among the most commonly reported adverse events with the use of palonosetron.