Drug Evaluation

Palonosetron for the treatment of chemotherapy-induced nausea and vomiting 1.

Introduction

2.

First-generation 5-HT3 receptor antagonists

3.

Palonosetron:

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second-generation serotonin (5-HT3) receptor antagonist 4.

Conclusion

5.

Expert opinion

Rudolph M Navari Cancer Care Program, World Health Organization, 202 Lincoln way East Mishawaka, IN, USA

Introduction: Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The introduction of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists has been a major factor in the improvement of the prevention of chemotherapy-induced acute and delayed emesis. Palonosetron, a second-generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity, and a different mechanism of action than the first-generation 5-HT3 receptor antagonists appears to be the most effective agent in this drug class. Areas covered: Palonosetron’s chemistry, pharmacodynamics, pharmacokinetics, metabolism, clinical efficacy, including comparison with other antiemetics, role in controlling nausea, potential role in multi-day chemotherapy and bone marrow transplantation, and overall safety are discussed. Expert opinion: The clinical data in the literature have established palonosetron as the 5-HT3 receptor antagonist of choice in terms of efficacy and safety for the prevention of CINV for patients receiving moderately or highly emetogenic chemotherapy. Three international guidelines have listed palonosetron as the preferred 5-HT3 receptor antagonist. Due to its higher efficacy, the use of palonosetron may be more cost effective compared to the generic firstgeneration 5-HT3 receptor antagonists. Clinical organizations’ pharmacy and formulary committees should consider efficacy when making recommendations for agents for the prevention of CINV. Keywords: 5-hydroxytryptamine-3 receptor antagonists, antiemetics, chemotherapy-induced nausea and vomiting, serotonin Expert Opin. Pharmacother. (2014) 15(17):2599-2608

1.

Introduction

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life and is perceived by patients as a major adverse effect of the treatment [1-3]. Increased risk of CINV is associated with the type of chemotherapy administered and specific patient characteristics [3]. CINV can result in serious complications, such as weakness, weight loss, electrolyte imbalance, dehydration, or anorexia, and is associated with a variety of complications, including fractures, esophageal tears, decline in behavioral and mental status, and wound dehiscence [1,3]. Patients who are dehydrated, debilitated, or malnourished, as well as those who have an electrolyte imbalance or those who have recently undergone surgery or radiation therapy, are at greater risk of experiencing serious complications from CINV [1-3]. The use of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists plus dexamethasone has improved the control of CINV [4]. Studies have demonstrated improvement in the control of CINV with the use of three agents, palonosetron (Box 1), a second-generation 5-HT3 receptor antagonist [4,5], aprepitant, the first agent 10.1517/14656566.2014.972366 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure

Palonosetron hydrochloride Launched Chemotherapy-induced nausea and vomiting 5 hydroxytryptamine 3 antagonist Alimentary, po Parenteral, intravenous N

O

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N H

Pivotal trial(s)

H HCI

[39-41]

available in the drug class of neurokinin-1 (NK-1) receptor antagonists [6], and olanzapine, an antipsychotic, which blocks multiple neurotransmitters in the central nervous system [7-9]. The primary endpoint used for studies evaluating various agents for the control of CINV has complete response (no emesis, no use of rescue medication) over the acute (24 h post-chemotherapy), delayed (24 -- 120 h), and overall (0 -- 120 h) periods [3]. Studies have shown that the combination of a 5-HT3 receptor antagonist, dexamethasone, and an NK-1 receptor antagonist have 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 [5,6]. Many of these same studies have measured nausea as a secondary endpoint and have demonstrated that nausea has not been well controlled [10,11]. Recommendations for the control of CINV with the use of the various antiemetic agents in different clinical settings have been described using guidelines established by the Multinational Association of Supportive Care in Cancer (MASCC) and the European Society of Medical Oncology [12], the American Society of Clinical Oncology (ASCO) [13], and the National Comprehensive Cancer Network (NCCN) guidelines [14]. 2.

First-generation 5-HT3 receptor antagonists

Serotonin receptors, specifically the 5-HT3 receptors, exist in the central nervous system and in the gastrointestinal (GI) tract [15,16]. The 5-HT3 receptor antagonists appear to act through both the central nervous system and the GI tract via the vagus and splanchnic nerves. The main toxicities of these 5-HT3 receptor antagonists consist only a mild headache, constipation, and occasional diarrhea [17]. Specific agents The introduction of 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and emesis, as well as post-operative and radiotherapy-induced nausea and vomiting, has resulted in an improvement in supportive 2.1

2600

care [17,18]. Table 1 shows the 5-HT3 receptor antagonists currently in use. The first-generation serotonin (5-HT3) receptor antagonists, dolasetron [17], granisetron [17], ondansetron [17], tropisetron [19], azasetron [20] and ramosetron [21], are equivalent in efficacy and toxicities when used in the recommended doses and compete only on an economic basis [22]. They have not been associated with major toxicities, with the most commonly reported adverse events being mild headache, constipation, and occasionally mild diarrhea [3]. Azasetron and ramosetron are not available in North America and Europe and have not been compared extensively to the other 5-HT3 receptor antagonists. They are marketed primarily in southeast Asia. A prolongation of cardiac conduction intervals has been reported for this class of compounds with dolasetron being more extensively studied than granisetron and ondansetron [23]. In 2010, the United States Food and Drug Administration (FDA) announced that the IV form of dolasetron should no longer be used to prevent CINV in any patient. Data suggested that dolasetron injection could increase the risk of developing a prolongation of the QT interval, which may potentially precipitate life-threatening ventricular arrhythmias [24-26]. In 2012, the FDA placed a restriction on the doses of IV ondansetron due to the risk of prolongation of the QT interval [27]. Patients who may be at particular risk for QT prolongation with ondansetron are those with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or patients taking concomitant medications that prolong the QT interval. The use of a single 32 mg IV dose of ondansetron should be avoided. Published information indicates that QT prolongation occurs in a dose-dependent manner, and specifically at a single IV dose of 32 mg. The lower dose IV regimen of 0.15 mg/kg every 4 h for three doses may be used in adults with CINV. However, no single IV dose of ondansetron should exceed 16 mg due to the risk of QT prolongation. The information does not change any of the recommended oral dosing regimens for ondansetron, including the single oral dose of 24 mg for CINV [27]. The first-generation 5-HT3 receptor antagonists have been very effective in the control of chemotherapy-induced emesis in the first 24 h post-chemotherapy (acute emesis), but have not been as effective against delayed emesis (24 -- 120 h postchemotherapy [28-30]. The first-generation 5-HT3 receptor antagonists alone do not add significant efficacy to that obtained by dexamethasone in the control of delayed emesis [29]. Hickok et al. [30]. reported that the first-generation 5-HT3s used in the delayed period were no more effective than prochlorperazine in controlling nausea. The antiemetic effects of prochlorperazine can be attributed to postsynaptic dopamine receptor blockade in the chemotherapy trigger zone. A meta analysis [29] showed that there was neither clinical evidence nor considerations of cost effectiveness to justify using the first-generation 5-HT3 antagonists beyond 24 h after chemotherapy for the prevention of delayed emesis. A number of studies have also demonstrated that there has been poor

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Palonosetron

Table 1. Serotonin antagonists and dosage before chemotherapy*. Antiemetic

Route

Dosage

Azasetron Granisetron

IV IV PO IV PO IV PO IV IV or PO

10 mg 10 µg/kg or 1 mg 2 mg (or 1 mg twice daily) 8 mg (restricted to £ 16 mg) 24 mg 0.25 mg 0.50 mg 0.30 mg 5 mg

Ondansetron Palonosetron

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Ramosetron Tropisetron

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

control of delayed nausea by the first-generation 5-HT3 receptor antagonists in patients receiving MEC or HEC [8,10,31,32]. The use of granisetron and dexamethasone in patients receiving HEC resulted in ‘no nausea’ in 25 -- 27% of patients [31]. The use of ondansetron plus dexamethasone in patients receiving MEC resulted in ‘no nausea’ in 33% of patients and ‘no significant nausea’ in 56% of patients [32].

sites [4,5]. The majority of evidence suggests that the GI site may be predominant [36]. 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) [4,5,37,38] and may have some efficacy in controlling delayed CINV compared to the firstgeneration 5-HT3 receptor antagonists. Palonosetron has demonstrated a 5-HT3 receptor binding affinity at least 30-fold higher than other 5-HT3 receptor antagonists [4,5]. Rojas et al. [38]. 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. Additional studies by Rojas et al. [38]. suggested that palonosetron triggers 5-HT3 receptor internalization and causes prolonged inhibition of receptor function. Differences in binding and effects on receptor function may explain some differences between palonosetron and the first-generation 5-HT3 receptor antagonists [4,5]. These differences may explain palonosetron’s efficacy in delayed CINV compared to the first-generation receptor antagonists [4,5]. Chemistry of palonosetron Palonosetron hydrochloride is an isoquinolone hydrochloride with an empirical formula of C19H24N2O HCl and a molecular weight of 332.87. Palonosetron exists as a single isomer. It is freely soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and 2-propanol. Palonosetron injection is a sterile, clear, colorless, non-pyrogenic, isotonic, buffered solution for IV administration. 3.1

Extended release transdermal granisetron (APF530)

2.2

A new formulation of a 5-HT3 receptor antagonist, transdermal granisetron, has been developed and approved by the FDA [33]. Three Phase I studies have evaluated the pharmacology of the transdermal delivery and have demonstrated that the plasma concentration is similar to levels obtained by 2 mg of oral granisetron administered every day during the same time period [33]. A randomized, double-blind, Phase III clinical trial evaluated the antiemetic efficacy of transdermal granisetron compared to oral granisetron in patients receiving MEC and HEC [34]. There was no significant difference in the control of acute or delayed emesis between transdermal and oral granisetron. The data demonstrated that transdermal granisetron was effective and safe in the control of acute emesis induced by MEC and HEC [34]. Grous et al. [35]. reported that two doses (5 and 10 mg) of sustained release granisetron (AFP530) were non-inferior to the second-generation 5-HT3 receptor antagonist palonosetron with respect to complete response (no emesis, no rescue) during the acute phase (24 h post-chemotherapy) in patients receiving MEC or HEC. The higher dose of APF530 (10 mg) was non-inferior to palonosetron during the delayed phase (24 -- 120 h post-chemotherapy) in patients receiving MEC.

Palonosetron: second-generation serotonin (5-HT3) receptor antagonist

3.

Palonosetron is a second-generation 5-HT3 receptor antagonist, which has antiemetic activity at both central and GI

Pharmacodynamics of palonosetron Palonosetron is a 5-HT3 receptor antagonist with a high binding affinity for this receptor and little or no affinity for other receptors. 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 [17]. Animal studies have demonstrated that chemotherapy agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates the 5-HT3 receptors located on the vagal afferents to initiate the vomiting reflex. Palonosetron demonstrated a 5-HT3 receptor binding affinity at least 30-fold higher than other 5-HT3 receptor antagonists (Table 2) [37]. 3.2

Pharmacokinetics and metabolism of palonosetron

3.3

After IV dosing of palonosetron in healthy subjects and cancer patients, an initial decline in plasma concentration is followed by a slow elimination from the body. Mean maximum plasma concentration and area under the concentration-time curve are generally dose-proportional over the dose range of 0.3 -- 90 µg/kg in healthy subjects and in cancer patients [37].

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R. M. Navari

Table 2. 5-hydroxytryptamine-3 receptor antagonists’ binding affinity and plasma half-life. Drug

pKi [-log(Ki)]

Half-life (hours)

Palonosetron Ondansetron Granisetron Dolasetron*

10.45 8.39 8.91 7.60

40 4 9 7.3

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

Palonosetron has a volume of distribution of ~8.3 ± 2.5 L/kg and is 62% bound to plasma proteins. Palonosetron is eliminated from the body through renal excretion and metabolic pathways. After a single IV dose of 10 µg/kg 14C palonosetron, ~80% of the dose was recovered within 144 h in the urine with palonosetron representing ~40% of the administered dose. The mean terminal elimination half-life is ~40 h (Table 2) [37]. Approximately 50% of palonosetron is metabolized to form two primary metabolites. Each of these metabolites has < 1% of the 5-HT3 receptor antagonist activity of palonosetron. The metabolic pathways are mediated via multiple CYP enzymes, including CYP2D6, and to a lesser extent, CYP3A and CYP1A2. Clinical pharmacokinetic parameters are not significantly different between poor and extensive CYP2D6 metabolizers. In vitro studies have indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5, nor did it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. The potential for clinically significant drug interactions with palonosetron appears to be low [37], indicating that the effectiveness of palonosetron should not vary among different individuals and not be affected by concurrent medications. In controlled clinical trials, palonosetron has been safely administered with corticosteroids, analgesics, antiemetics, antispasmodics, and anticholinergic agents [30,37,39-44]. Population pharmacokinetic analysis did not reveal any differences between cancer patients ‡ 65 years of age and younger patients. Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetics and hepatic impairment does not significantly affect total body clearance of palonosetron compared to healthy patients. Therefore, dosage adjustment is not necessary for patients with renal or hepatic impairment [37,45]. As a number of patients with malignancies may have some degree of renal or hepatic impairment, the properties of palonosetron allow it to be used in these patients. Clinical efficacy of palonosetron in single-day chemotherapy

3.4

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 firstgeneration 5-HT3 receptor antagonists alone in patients receiving MEC [39,40]. In patients receiving HEC, 2602

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 [41]. In patients receiving HEC, 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) [31]. 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 [42,43]. There was also no difference in the control of nausea with the addition of the additional days of dexamethasone. Boccia et al. [44] recently demonstrated that oral palonosetron had similar efficacy and safety as IV palonsetron for the prevention of acute CINV in patients receiving MEC. 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. [46]. 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. Schwartzberg et al. [47] concluded that palonosetron is more effective than the first-generation 5-HT3 receptor antagonists in controlling CINV in the delayed and overall post-chemotherapy periods based on a pooled analysis of Phase III clinical studies of palonosetron versus ondansetron, dolasetron, and granisetron. In an additional review, Popovic et al. [48] concluded that palonosetron is safer and more efficacious than the other 5-HT3 receptor antagonists. 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 [39-44]. 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 [4,5,48-50]. The published clinical studies on palonosetron have prompted the NCCN guidelines to recommend palonosetron as the preferred 5-HT3 receptor antagonist in patients treated with HEC [14], and the ASCO [13], NCCN [14], and MASCC [12] guidelines to recommend palonosetron for the prevention of acute and delayed CINV caused by MEC. 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.

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Palonosetron

Prevention and treatment of nausea with palonosetron

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3.5

The mechanism of chemotherapy-induced nausea is not well known in terms of neurotransmitters and neuroreceptors and appears to be a supratentorial subjective experience [10,11]. The mechanisms of vomiting are better understood based on animal models and appear to be a brainstem reflex [11]. The current data in the literature from multiple large studies suggest that the 5-HT3 receptor antagonists have not had a major effect on the control of nausea in patients receiving either MEC or HEC, despite the marked improvement in the control of emesis with these agents [10]. It appears that the serotonin 5-HT3 receptor may not be of major importance in mediating nausea. In a retrospective multistudy analysis, Morrow et al. [51] suggested that palonosetron may be more effective than the first-generation 5-HT3 receptor antagonists in the prevention of nausea, but there was no statistically significant difference among the first-generation 5-HT3 receptor antagonists and palonosetron in the prevention of nausea in the multistudy analysis. Saito et al. [31] reported an improvement in ‘no nausea’ in the delayed and overall periods after HEC in patients who received palonosetron plus dexamethasone compared to patients receiving granisetron plus dexamethasone, but the magnitude of the control was low (Table 3). Table 3 summarizes Phase II and III studies of various serotonin receptor antagonists on the prevention of chemotherapy-induced nausea [8,9,31,32,42,43,52,53]. A number of studies have reported that olanzapine has demonstrated very good control of both emesis and nausea in patients receiving either MEC or HEC [7-9,52-54]. In a randomized, doubleblind, Phase III trial, patients receiving HEC were randomized to olanzapine, palonosetron, and dexamethasone versus aprepitant, palonosetron, and dexamethasone [9]. The complete response (no emesis, no rescue) was similar for the two CINV preventative regimens, but the control of nausea in the delayed and overall periods was significantly improved with the olanzapine regimen [9]. It is known that olanzapine blocks multiple neurotransmitters: dopamine at D1, D2, D3, D4 brain receptors, serotonin at 5-HT2a, 5-HT2c, 5-HT3, 5-HT6 receptors, catecholamines at a1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors [55,56]. There are no current definitive animal or human data, which point to which of these receptors may be more important in controlling chemotherapy-induced nausea. The 5-HT2C receptor has been associated with appetite and weight gain [57], and this receptor may be involved in the control of nausea. Clinical efficacy of palonosetron in multi-day chemotherapy

3.6

Due to its efficacy in the prevention of both acute and delayed CINV, palonosetron has high potential for preventing and controlling CINV in multi-day chemotherapy and bone

marrow transplantation. There have been few studies on the use of palonosetron in the prevention of CINV in multi-day chemotherapy or bone marrow transplantation. Table 4 summarizes the small number of Phase II studies. Palonosetron on days 1, 3, and 5 along with a regimen of dexamethasone was safe and well tolerated and reported to effectively control both nausea and emesis in patients undergoing 5-day cisplatin-based chemotherapy for testicular cancer [58]. A regimen of palonosetron, aprepitant, and dexamethasone was also reported to control nausea and emesis in testicular germ cell tumor patients receiving a 5-day cisplatin-based combination chemotherapy [59]. Complete control in the acute period (24 h post chemotherapy) was improved compared to historical controls receiving ondansetron in 58 patients undergoing multiple-day high-dose chemotherapy who received palonosetron every other day plus daily dexamethasone [60]. Three studies used palonosetron in patients undergoing high-dose chemotherapy prior to bone marrow transplantation and reported improved control of CINV compared to historical control patients who received first-generation 5-HT3 receptor antagonists [61-63]. Safety and tolerability of palonosetron Results from the Phase II dose-ranging study and Phase III comparative studies in patients receiving MEC and HEC were the basis for approval of palonosetron by the FDA [37,39-41]. In these studies, patients were exposed to a wide range of palonosetron doses, up to 25 times the approved palonosetron dose of 0.25 mg. The adverse reactions reported were the most common reactions reported for the 5-HT3 receptor antagonist class, headache, and constipation. All other reactions occurred at an incidence of £ 1% in patients treated with 0.25 mg of palonosetron [44-50]. There were no clinically relevant differences seen among palonosetron ondansetron, or dolasetron in laboratory, electrocardiographic, or vital sign changes [23,49,50]. A clinical study in male and female volunteers showed that the cardiac profile of palonosetron is the same as placebo. There were no electrocardiographic or dose response effects, including QTc prolongation, of palonosetron up to a 2.25 mg IV dose, a ninefold safety margin [64]. The safety of palonosetron administered over repeated cycles of HEC was demonstrated in a study of 538 patients [50]. Palonosetron at three times the approved dose was well tolerated over repeated cycles with no unexpected adverse events. There were no clinically relevant differences among cycles, and the number of adverse reactions did not increase throughout repeated chemotherapy cycles [50]. 3.7

Regulatory affairs Palonosetron hydrochloride injection is distributed by Eisai, Inc., in the United States and is indicated for the prevention of acute nausea and vomiting associated with initial and repeat courses of MEC and HEC and for the prevention of 3.8

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Table 3. Phase II and III trials of various serotonin receptor antagonists for the prevention of chemotherapyinduced nausea. Study

Phase II or III

No. patients

Saito et al. (2009) [31]

HEC

III

1114

Navari et al. (2011) [9]

HEC

III

257

III

866

III

44

III

334

III

300

II III III

32 229

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Chemotherapy

Celio et al. (2012) [43] Aapro et al. (2010) [42] Navari et al. (2007) [52] Tan et al. (2009) [8]

Cyclo + Doxo/ Epi HEC, MEC

MEC Cyclo + Doxo/ Epi MEC MEC HEC

No nausea, delayed (%)

No nausea, overall (%)

Palo + Dex: 38* Gran + Dex: 27 OPD: 69* APD: 38 Ond + Dex: 36

Palo + Dex: 32* Gran + Dex: 25 OPD: 69* APD: 38 Ond + Dex: 33

OLN + 5-HT3, Dex, Aprepitant 64* 5-HT3, Dex, Aprepitant 23 Palo + Dex1: 57 Palo + Dex3: 62 Palo + Dex1: 50 Palo + Dex3: 55 OPD: 78 OAD: 83* AD: 58 OAD: 70* AD: 30

OLN + 5-HT3, Dex, Aprepitant 59* 5-HT3, Dex, Aprepitant 23 Palo + Dex1: 52 Palo + Dex3: 57 Palo + Dex1: 47 Palo + Dex3: 50 OPD: 78 OAD: 83* AD: 56 OAD: 70* AD: 28

*p < 0.01. 5-HT3: 5-hydroxytryptamine-3; AD: Azasetron; APD: Aprepitant, palonosetron, dexamethasone; Cyclo: Cyclophosphamide; Dex: Dexamethasone; Dex1: 1 day of dexamethasone; Dex3: 3 days of dexamethasone; Doxo: Doxorubicin; Epi: Epirubicin; Gran: Granisetron; HEC: Highly emetogenic chemotherapy; MEC: Moderately emetogenic chemotherapy; OAD: Olanzapine, azasetron, dexamethasone; OLN: Olanzapine; Ond: Ondansetron; OPD: Olanzapine, palonosetron, dexamethasone; Palo: Palonosetron.

Table 4. Palonosetron in multi-day high-dose chemotherapy. Study

Chemotherapy

Phase II No. Antiemetic or III patients prophylaxis

Einhorn et al. (2007) [58] Hamada et al. (2014) [59] Mirabile et al. (2014) [60]

5-day cisplatin 5-day cisplatin Multi-day, high dose

II II II

41 30 58

Ripaldi et al. (2010) [61]

Multi-day, high dose, BMT II

43

Rzepecki et al. (2009) [62] Multi-day, high dose, BMT II Multi-day, high dose, BMT II Musso et al. (2010) [63]

Chemotherapy-induced nausea and vomiting

Palo + Dex Well controlled Palo + Dex + Apr 90% complete response in first cycle Palo + Dex Complete control improved compared to historical Ond Palo Improved compared to historical 5-hydroxytryptamine-3s Palo Improved compared to historical Ond Palo + Dex 36% Complete response

46 134

BMT: Bone marrow transplant; Dex: Dexamethasone; Ond: Ondansetron; Palo: Palonosetron.

delayed nausea and vomiting associated with initial and repeat courses of MEC. Palonosetron has been on the market in the United States since September, 2003. In Europe, palonosetron is indicated for the prevention of acute nausea and vomiting associated with HEC and for the prevention of nausea and vomiting associated with MEC. In Europe, the product has been approved centrally as of March 2005 but the effective launch in each country has occurred in different periods after discussions with local authorities. Palonosetron is currently present in the markets of Asia, the Middle East, South Africa, and Latin America with indications similar to those in the United States. 2604

4.

Conclusion

Palonosetron hydrochloride is an isoquinolone hydrochloride, which exists as a single isomer, is freely soluble in water, and is available orally and as an IV injection. Palonosetron is a 5-HT3 receptor antagonist with a high binding affinity for this receptor and little or no affinity for other receptors. It has a very high binding affinity for the 5-HT3 receptor and a half-life of 40 h. Animal studies have suggested that palonosetron exhibits allosteric binding and positive cooperativity when binding to the 5-HT3 receptor and may affect the receptor function. This binding appears to be significantly different

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Palonosetron

from the simple bimolecular binding for both granisetron and ondansetron. Palonosetron is eliminated from the body through renal excretion and metabolic pathways. After a single IV dose of 10 µg/kg 14C palonosetron, ~80% of the dose was recovered within 144 h in the urine with palonosetron representing ~40% of the administered dose. Approximately 50% of palonosetron is metabolized to form two primary metabolites. Each of these metabolites has < 1% of the 5-HT3 receptor antagonist activity of palonosetron. The potential for clinically significant drug interactions with palonosetron appears to be low. In controlled clinical trials, palonosetron has been safely administered with corticosteroids, analgesics, antiemetics, antispasmodics, and anticholinergic agents. Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetics and hepatic impairment does not significantly affect total body clearance of palonosetron compared to healthy patients. Therefore, dosage adjustment is not necessary for patients with renal or hepatic impairment. Randomized, double-blind, 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 ondansetron and granisetron alone in patients receiving MEC. 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. In additional studies in patients receiving HEC, palonosetron plus dexamethasone was significantly better than granisetron and dexamethasone in the delayed period complete response. Differences in binding and effects on receptor function may explain some differences between palonosetron and the first-generation 5-HT3 receptor antagonists. The current data in the literature from multiple large studies suggest that the 5-HT3 receptor antagonists have not had a major effect on the control of nausea in patients receiving either MEC or HEC, despite the marked improvement in the control of emesis with these agents. The clinical studies suggest that palonosetron may be more effective in the control of nausea than the first-generation 5-HT3 receptor antagonists due to its improved efficacy in the delayed period, but the magnitude of nausea control is relatively low. Due to its efficacy in the prevention of both acute and delayed CINV, palonosetron has high potential for preventing and controlling CINV in multi-day chemotherapy and bone marrow transplantation. Preliminary studies have begun to explore this use. The safety and tolerability of palonosetron have 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.

The published clinical studies on palonosetron have prompted the NCCN guidelines [14] to recommend palonosetron as the preferred 5-HT3 receptor antagonist in patients treated with HEC, and the ASCO [13], NCCN [14], and MASCC [12] guidelines to recommend palonosetron for the prevention of acute and delayed CINV caused by MEC. 5.

Expert opinion

The large number of high-quality clinical studies in the current literature has established that palonosetron is equivalent to the first-generation 5-HT3 receptor antagonists in the control of emesis in the first 24 h post-chemotherapy (acute period) and more efficacious than first-generation 5-HT3 receptor antagonists in the control of emesis in days 2 -- 5 (delayed period) post-chemotherapy in patients receiving MEC or HEC. Palonosetron has been in use since 2003, and no serious adverse events have been reported. Its safety profile is similar to the first-generation 5-HT3 receptor antagonists and its use in a single cycle or multiple cycles of chemotherapy has not resulted in any adverse events. There have been no reports of abnormal electrocardiographic or dose response effects, including QTc prolongation, of palonosetron up to a 2.25 mg IV dose, a ninefold safety margin. Palonosetron may have some advantage over the firstgeneration 5-HT3 receptor antagonists in the prevention of chemotherapy-induced nausea, but the advantage is small, and it appears that the 5-HT3 receptor antagonists as a drug class do not appear to be effective anti-nausea agents. New agents are needed for the prevention of chemotherapyinduced nausea. Recent studies and current clinical trials with olanzapine appear to be promising. The measurement of nausea in the published studies on CINV prophylaxis has been primarily with a visual analog scale. As nausea is a subjective, multi-component symptom, a more comprehensive measure may be needed. Due to its long half-life, high binding affinity, and the apparent unique effect on the 5-HT3 receptor, palonosetron has potential to be effective in the clinical settings of multiday chemotherapy and bone marrow transplantation. Very few studies have been performed in these clinical situations and randomized, double-blind, Phase III studies are needed comparing the use of palonosetron to the standard of care. In May, 2014, the FDA approved the use of palonosetron for the prevention of CINV in children aged 1 month to < 17 years [65]. This is the first product to be approved for acute CINV prevention in children aged 1 -- 6 months, which is significant because peak cancer incidence among children occur during the first year of life. The published clinical studies on palonosetron have prompted the international guideline groups to recommend palonoseteron 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. These recommendations have been based on the

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clinical studies, which compared single agent palonosetron to single agent ondansetron or single agent dolasetron, as well as the comparison of palonosetron plus dexamethasone to ondansetron plus dexamethasone. There have been no published studies on the comparison of palonosetron plus dexamethasone plus aprepitant to the first-generation 5-HT3 plus dexamethasone plus aprepitant. Despite the recommendation of the international guideline groups for the use of palonosetron as the preferred 5-HT3 receptor antagonist, some clinical organizations continue to use the first-generation 5-HT3 receptor antagonist for the prevention of CINV. This appears to be a decision of the organization’s pharmacy or formulary committee based on economic issues preferring to utilize a generic first-generation 5-HT3 receptor antagonist rather than palonosetron. The estimated cost of the various 5-HT3 receptor antagonists for one cycle of chemotherapy is: $406 -- 423 for palonosetron, Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Declaration of interest The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Affiliation Rudolph M Navari1,2 MD PhD FACP 1 Director, Cancer Care Program, Eastern Europe World Health Organization 2 President, South Bend Medical Services Corp., 202 Lincolnway East, Suite #105, Mishawaka, IN 46544, USA Tel: +1 574 252 7225; E-mail: [email protected]