The current status of the use of palonosetron

Abstract

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in the quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient characteristics (female gender, younger age, low alcohol consumption, history of motion sickness) are the major risk factors for CINV. Palonosetron, a second-generation 5-hydroxytryptamine 3 (5-HT₃) receptor antagonist, has antiemetic activity at both central and gastrointestinal sites. In comparison to the first-generation 5-HT₃ receptor antagonists, it has a higher potency, a significantly longer half-life, and a different molecular interaction with 5-HT₃ receptors. Palonosetron has been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. Compared to the first-generation 5-HT₃ receptor antagonists, palonosetron in combination with dexamethasone has demonstrated better control of delayed CINV in patients receiving highly emetogenic chemotherapy and had a similar safety profile. Due to its efficacy in controlling both acute and delayed CINV, palonosetron may be very effective in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.

Keywords::

• antiemetics
• chemotherapy
• nausea and emesis
• palonosetron

Chemotherapy-induced nausea and vomiting (CINV) is a significant clinical issue which has been improved by the introduction of the 5-HT₃ receptor antagonist drug class [1]. Studies have shown that the combination of a 5-HT₃ receptor antagonist, dexamethasone, with or without a neurokinin-1 (NK-1) receptor antagonist, has improved the control of emesis in patients receiving either highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) over a 120-h period following chemotherapy administration [1,2]. Although emesis has been improved in the acute period with the use of the 5-HT₃ receptor antagonists and in the delayed period with the use of the NK-1 receptor antagonists, many of these same studies have measured nausea as a secondary endpoint and have demonstrated that nausea has not been well controlled [3]. Clinical trials have demonstrated that with the use of guideline-directed prophylactic antiemetics, in patients receiving HEC or MEC, the control of emesis and nausea is 65 – 75% and 35 – 50%, respectively, over the 120-h period post-chemotherapy [3-5].

The first-generation 5-HT₃ receptor antagonists, dolasetron, granisetron, ondansetron, tropisetron, azasetron, and ramosetron are equivalent in efficacy when used in the recommended doses and share a similar toxicity profile (Table 1) [1,3].

Table 1. Serotonin antagonists and dosage before chemotherapy*.

Antiemetic	Route	Dosage
Azasetron	IV	10 mg
Dolasetron (not recommended for use per FDA)	IV PO	100 mg or 1.8 mg/kg 100 mg
Granisetron	IV PO	10 µg/kg or 1 mg 2 mg (or 1 mg twice daily)
Ondansetron	IV PO	8 mg (restricted to < 16 mg) 24 mg
Palonosetron	IV PO	0.25 mg 0.50 mg
Ramosetron	IV	0.30 mg
Tropisetron	IV or PO	5 mg

*The same doses are used for highly and moderately emetic chemotherapy.

Azasetron and ramosetron are not available in North America and Europe, are marketed primarily in Southeast Asia, and have not been compared extensively to the other 5-HT₃ receptor antagonists.

Although the first-generation 5-HT₃ receptor antagonists have been effective in the control of acute emesis (first 24 h post-chemotherapy), they have not been shown to improve delayed nausea or emesis in patients receiving MEC or HEC [3,6].

Dexamethasone alone provides some control of delayed emesis and nausea, but this modest effect is not improved with the addition of the first-generation 5-HT₃ receptor antagonists in the delayed period [6].

There have been few, if any, serious Grade 3 or 4 toxicities or adverse events related to the clinical use of the first-generation 5-HT₃ receptor antagonists [1,3], but the U.S. Food and Drug Administration (FDA) has recently recommended that dolasetron no longer be used to prevent CINV and has placed a dose restriction of < 16 mg on intravenous ondansetron due to a potential of prolongation for the QTc interval and the potential precipitation of ventricular arrhythmias [3].

Palonosetron is a second-generation 5-HT₃ receptor antagonist which has antiemetic activity at both central and GI sites, although the majority of evidence suggests a peripheral mechanism [7]. In comparison to the first-generation 5-HT₃ receptor antagonists, it has a higher potency, a significantly longer half-life, and a different molecular interaction with 5-HT₃ receptors (Table 2) [1,8].

Table 2. 5-HT₃ receptor antagonist's binding affinity and plasma half-life.

Drug	pK i [-log(K i)]	Half-life (h)
Palonosetron	10.45	40
Ondansetron	8.39	4
Granisetron	8.91	9
Dolasetron*	7.60	7.3

*Half-life reported for hydrodolasetron, the active metabolite of dolasetron.

Palonosetron has demonstrated a 5-HT₃ receptor binding affinity at least 30-fold higher than other 5-HT₃ receptor antagonists [1]. Rojas et al. [8] reported that palonosetron exhibited allosteric binding and positive cooperativity when binding to the 5-HT₃ receptor compared to simple bimolecular binding for both granisetron and ondansetron. Palonosetron appears to trigger 5-HT₃ receptor internalization and causes prolonged inhibition of receptor function [8]. Differences in binding and effects on receptor function may explain some differences between palonosetron and the first-generation 5-HT₃ receptor antagonists [1]. These differences may explain palonosetron's efficacy in delayed CINV compared to the first-generation receptor antagonists [1,8-11].

Phase III comparative studies suggest that the use of palonosetron alone improves the complete response rate of acute and delayed emesis, when compared with the use of the first-generation 5-HT₃ receptor antagonists alone in patients receiving MEC [10,11]. In patients receiving HEC, palonosetron was as effective as ondansetron in the prevention of acute CINV and with dexamethasone pre-treatment, palonosetron was significantly better than ondansetron in the overall 120-h post-treatment period [9].

In patients receiving HEC, a recent study showed that palonosetron plus dexamethasone was significantly better than granisetron and dexamethasone in delayed complete response and control of nausea, but there was a low number of patients with no nausea with either regimen (no nausea, overall period: 31.9% palonosetron group; 25.0% granisetron group) [12].

Two studies reported that palonosetron plus 1 day of dexamethasone was as effective as palonosetron plus 3 days of dexamethasone in the prevention of acute and delayed CINV in patients receiving MEC [13,14]. Boccia et al. recently demonstrated that oral palonosetron had similar efficacy and safety as intravenous palonosetron for the prevention of acute CINV in patients receiving MEC [15].

A Phase II study using olanzapine in combination with palonosetron and dexamethasone showed promise in controlling acute and delayed emesis and nausea in patients receiving MEC and HEC [3]. A randomized Phase III trial compared olanzapine, palonosetron and dexamethasone to aprepitant, palonosetron, and dexamethasone in patients receiving HEC. The control of emesis was similar for both regimens over the 120-h post-chemotherapy period, but the olanzapine regimen was significantly better than the aprepitant regimen in the control of nausea in the delayed and overall periods (no nausea, overall period: 69% olanzapine group; 38% aprepitant group) suggesting that olanzapine is an effective agent for the control of nausea [5]. This study and other Phase III clinical trials have demonstrated that aprepitant has not been effective in controlling nausea [3].

In a systematic review and meta-analysis of all randomized controlled trials comparing a single dose of palonosetron with other 5-HT₃ receptor antagonists, Botrel et al. [16] concluded that palonosetron was more effective than the first-generation receptor antagonists in preventing acute and delayed CINV in patients receiving MEC or HEC, regardless of the use of concomitant corticosteroids. In an additional systematic review of the medical literature, Fabi and Malaguti [17] reported that palonosetron was the only serotonin receptor antagonist approved for the prevention of delayed CINV caused by MEC.

The safety and tolerability of palonosetron has been well documented in multiple, large Phase III trials. There were no clinically relevant differences seen among palonosetron, ondansetron, or dolasetron in laboratory, electrocardiographic, or vital sign changes over multiple cycles of chemotherapy [10,11,16-18]. The adverse reactions reported were the most common reactions reported for the 5-HT₃ receptor antagonist drug class. There have been no reports of any adverse cardiac events with palonosetron, specifically no prolongation of the QTc interval in healthy volunteers or patients receiving repeated cycles of emetogenic chemotherapy [1,18,19].

Based on the clinical studies, palonosetron is highly effective in controlling acute and delayed CINV in patients receiving either MEC or HEC. Compared to the first-generation 5-HT₃ receptor antagonists, palonosetron has equivalent efficacy in controlling acute CINV and is more effective in controlling delayed CINV. In addition to the FDA indications for the prevention of acute and delayed CINV which occurred in July 2003, palonosetron received FDA approval in March 2008 for the prevention of post-operative nausea, and vomiting based on two randomized, double-blind studies [1].

The published clinical studies on palonosetron have prompted the international guideline groups to recommend palonosetron as the preferred 5-HT₃ receptor antagonist for the prevention of acute nausea and vomiting for patients receiving HEC and for the prevention of delayed nausea and vomiting for patients receiving MEC [20].

Two recent studies have reported that the complete response rates for both acute and delayed CINV were maintained with the single intravenous dose of palonosetron in patients receiving repeated courses of HEC [18].

Due to its efficacy in both acute and delayed CINV, palonosetron has high potential for controlling CINV in the settings of multi-day chemotherapy and bone marrow transplantation. Two studies have demonstrated the efficacy of palonosetron in controlling CINV in patients receiving multiple-day chemotherapy [21].

Palonosetron should be further studied for the control of nausea and emesis in combination with dexamethasone, aprepitant, and/or olanzapine. Clinical trials have demonstrated that dexamethasone and aprepitant are not effective antinausea agents and that nausea remains a persistent patient issue. Recent studies also suggest that palonosetron and olanzapine may have significant potential in controlling nausea. Future research may determine if nausea and emesis can be better controlled with these combinations. Such studies may not only provide additional options for the control of acute and delayed CINV, but may also provide new information on the mechanism of CINV.

In summary, palonosetron is a second-generation 5-HT₃ receptor antagonist that has a mechanism of action which is markedly different from the first-generation 5-HT₃ receptor antagonists. Based on Phase II and Phase III clinical trials, it is equivalent to the first-generation 5HT₃ receptor antagonists in controlling acute CINV, but has a higher efficacy in delayed CINV. Palonosetron is recommended as the preferred 5-HT₃ receptor antagonist by a number of international guidelines for patients receiving MEC or HEC. The effective control of CINV in the 120-h post-chemotherapy will significantly improve the quality of life of patients post-chemotherapy and reduce or eliminate the costly post-chemotherapy clinic or emergency department visits. Due to its efficacy in delayed CINV, it may have potential in controlling CINV in patients receiving multiple-day chemotherapy and bone marrow transplantation. Future clinical trials will determine the effectiveness of palonosetron in these clinical settings. There are no other second-generation 5-HT₃ receptor antagonists on the market, and there is no information available on other second-generation agents in development.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.