Combination Of Palonosetron Research Articles

Aprepitant, Granisetron and Dexamethasone Versus Palonosetron and Dexamethasone for Cisplatin-Induced Nausea and Vomiting in Patients with Upper Gastrointestinal Cancer: a Randomized Crossover Phase Ii Trial (Kdog 1002)

ABSTRACT Aim: Large-scale clinical studies on chemotherapy-induced nausea and vomiting (CINV) induced by highly emetogenic chemotherapy (HEC) showed that antiemetic therapy with a 3-drug combination of aprepitant, granisetron and dexamethasone (AGD) or a 2-drug combination of palonosetron and dexamethasone (PD) were superior to conventional antiemetic therapy a 5HT3 receptor antagonist and dexamethasone. But the AGD and PD regimens have not been compared. We performed a randomized crossover trial to compare the efficacy of AGD and PD in HEC. Methods: The subjects were patients with esophageal or gastric cancer who underwent HEC including ≥60 mg/m2 cisplatin as first-line treatment. Patients were randomly assigned into groups treated with AGD (oral aprepitant 125 mg on day 1, 80 mg on days 2–3; intravenous granisetron 3 mg on day 1; intravenous dexamethasone (D) 6.6 mg on day 1 and oral D 4 mg on days 2-3) or PD (intravenous palonosetron 0.75 mg on day 1; intravenous D 13.2 mg on day 1 and oral D 8 mg on days 2-3). The antiemetic therapies were crossed-over in the second course. The primary endpoint was a complete response (CR: defined as no emetic episodes and no requirement for rescue medication) in the overall phase (0-120 h) during the first course. The planned sample size of 80 patients provided 80% power to detect a 30% improvement in CR with a two-sided alpha of 0.05. Results: Eighty-fifth patients were enrolled in the study and 84 were evaluable. Baseline factors were well-balanced between the two groups. The CR rate did not differ significantly between the two groups, but the frequency of no vomiting was significantly higher in the AGD group (Table 1). Regarding patient's preference after the second course, 41.0% of patients preferred AGD, 19.7% preferred PD, and 39.3% indicated no preference. Based on a QOL survey, the frequency of no or minimal impact on daily life in the vomiting domain was significantly higher in the AGD group (79.1% vs. 53.7%; p = 0.014). Persentages of patients reaching efficacy endpoints AGD, N=43 PD, N=41 p value Complete response 67.4% 58.5% 0.399 No vomiting 81.4% 58.5% 0.025 No nausea 39.5% 39.0% 0.962 No rescue 674% 75.6% 0.409 Conclusions: The primary endpoint of CR was not achieved, but AGD combination therapy seems to more effective than PD therapy for prevention of HEC-induced CINV. Disclosure: All authors have declared no conflicts of interest.

Synergistic effect of 5-hydroxytryptamine 3 and neurokinin 1 receptor antagonism in rodent models of somatic and visceral pain.

Synergistic activity has been observed between serotonergic 5-hydroxytryptamine 3 (5-HT3) and tachykinergic neurokinin 1 (NK1) receptor-mediated responses. This study investigated the efficacy of a 5-HT3 antagonist, palonosetron, and a NK1 antagonist, netupitant, alone or in combination in rodent models of somatic and visceral colonic hypersensitivity. In a rat model of experimental neuropathic pain, somatic hypersensitivity was quantified by the number of ipsilateral paw withdrawals to a von Frey filament (6g). Electrophysiologic responses were recorded in the dorsal horn neurons after mechanical or thermal stimuli. Acute colonic hypersensitivity was induced experimentally in rats by infusing dilute acetic acid (0.6%) directly into the colon. Colonic sensitivity was assessed by a visceromotor behavioral response quantified as the number of abdominal contractions in response to graded isobaric pressures (0-60 mm Hg) of colorectal distension. Palonosetron or netupitant was administered alone or in combination via oral gavage. When dosed alone, both significantly reduced somatic sensitivity, decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation, and caused significant (P < 0.05) inhibition of colonic hypersensitivity in a dose-dependent manner. The combined administration of palonosetron and netupitant at doses that were ineffective alone significantly reduced both somatic and visceral sensitivity and decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation. In summary, the combination of palonosetron with a NK1 receptor antagonist showed synergistic analgesic activity in rodent models of somatic and visceral hypersensitivity, and may prove to be a useful therapeutic approach to treat pain associated with irritable bowel syndrome.

Palonosetron (PAL) in combination with 1-day versus 3-days dexamethasone (DEX) to prevent nausea and vomiting in patients receiving paclitaxel and carboplatin (TC).

9608 Background: According to current guidelines the combination of PAL and 3-days DEX is the standard antiemetic treatment in pts receiving TC. However, PAL has prolonged efficacy in preventing de...

Palonostron with aprepitant plus dexamethasone to prevent chemotherapy-induced nausea and vomiting (CINV) during gemcitabine/cisplatin (GC) in urothelial cancer (UC) patients: A multi-institutional retrospective study in Japan.

362 Background: GC combination chemotherapy of is a standard regimen for advanced UC. Although this is a highly emetogenic chemotherapy, there has been no study concerning antiemetic prophylaxis for CINV during GC. The aims of this study were to evaluate CINV during GC and to compare the antiemetic efficacy of the triple combination of palonosetron, aprepitant and dexamethasone with that of our old regimen using first-generation 5-HT3 receptor antagonists and dexamethasone. Methods: We conducted a retrospective multi-institutional review of the medical records of 122 patients who received GC for advanced urothelial cancer between February 2005 and January 2012. Uncontrolled CINV events were identified through records of nausea and vomiting, additional infusion, rescue medications, and/or records of food intake. Nausea, vomiting, and anorexia were classified using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Results: A total of 75 and 47 patients were treated with first-generation 5-HT3 receptor antagonists (ondansetron or granisetron) plus dexamethasone (group 1) and palonosetron with dexamethasone plus aprepitant (group 2), respectively. There was no significant difference in age, sex, or the dose of cisplatin between the 2 groups. Patients in group 2 had significantly higher CR (defined as no emetic episodes and no rescue medication use) rates than those in group 1 during the overall phase in the first cycle (85.7% versus 65.3%, p=0.012) and all cycles (78.7% versus 50.7%, p=0.0019) of GC. Patients in group 2 were more likely to achieve more favorable CINV control, e.g., a lower grade of nausea, vomiting, or anorexia, lower incidence of rescue therapy required, and shorter time to become CINV-free, than patients in group 1. Conclusions: This study shows that palonosetron in combination with aprepitant and dexamethasone is more effective to prevent chemotherapy-induced nausea and vomiting in UC patients treated with GC than first-generation 5-HT3 receptor antagonists plus dexamethasone.

SEOM guide to antiemetic prophylaxis in cancer patients treated with chemotherapy 2013

Chemotherapy-induced emesis (CIE) both in the form of nausea and vomiting is one of the adverse effects most feared by patients who receive treatment, and one of the factors that most affect their quality of life and limit their functional capacity for everyday activities. Chemotherapy-induced emesis can result from many factors, depending on the treatment and the patients themselves. The best treatment for CIE is prevention, based on the use of drugs aimed at inhibiting the signal of certain neurotransmitters involved in the process. Antiemetic prophylaxis for chemotherapy of high-emetogenous potential lasting 1 day includes a combination of anti-5-HT3, neurokinin-1 inhibitors and dexamethasone. Antiemetic prophylaxis for chemotherapy of moderate-emetogenous potential lasting 1 day includes a combination of palonosetron and dexamethasone. Prophylaxis is not recommended for chemotherapy with minimal emetogenous potential. In the case of unforeseen or refractory emesis the use of olanzapine, metoclopramide or phenothiazine should be considered.

P1-126 - Palonostron with Aprepitant–Dexamethasone to Prevent Chemotherapy-Induced Nausea and Vomiting During Gemcitabine/Cisplatin in Urothelial Cancer Patients

ABSTRACT Background The combination of gemcitabine and cisplatin (GC) is a standard regimen for advanced urothelial cancer (UC). Although this is a highly emetogenic chemotherapy, there has been no study concerning antiemetic prophylaxis for chemotherapy-induced nausea and vomiting (CINV) during GC. The aims of this study were to evaluate CINV during GC and to compare the antiemetic efficacy of the triple combination of palonosetron, aprepitant and dexamethasone with that of our old regimen using ondansetron and dexamethasone. Methods We conducted a retrospective review of the medical records of 52 patients who received GC for advanced urothelial cancer between February 2005 and January 2012. Uncontrolled CINV events were identified through records of nausea and vomiting, additional infusion, rescue medications and/or records of food intake. Nausea, vomiting and anorexia were classified using the Common Terminology Criteria for Adverse Events (CTCAE) ver4.0. Results A total of 23 and 29 patients were treated with ondansetron–dexamethasone (group 1) and palonosetron with dexamethasone–aprepitant (group 2), respectively. There was no significant difference in age, gender or the dose of cisplatin between the two groups. Patients in group 2 were more likely to achieve more favorable CINV control, e.g. a lower grade of nausea, vomiting or anorexia, lower incidence of rescue therapy required and shorter time to become CINV-free, than patients in group 1. Conclusions This study shows that palonosetron in combination with aprepitant and dexamethasone is more effective to prevent chemotherapy-induced nausea and vomiting in UC patients treated with GC than ondansetron–dexamethasone.

Palonosetron (PALO) plus 1-day versus 3-day dexamethasone (DEX) with or without aprepitant against delayed nausea (DN): Pooled analysis for 554 women receiving highly emetogenic chemotherapy (HEC).

9133 Background: Nausea is more difficult to control than vomiting, because the incidence of the symptom continues to rise over the days after chemotherapy. This post-hoc analysis addressed two questions: 1) Does PALO plus single-dose DEX result in suboptimal control of DN when compared to the same regimen with additional DEX doses? 2) Is the combination of PALO, DEX, and aprepitant a more effective coverage against DN? Methods: The analysis was based upon outcomes in chemo-naïve women (median age =52) with solid tumors (89% breast) enrolled in two Phase III and two Phase II trials of HEC (AC combination or cisplatin). Patients received the following regimens: 1) PALO 0.25 mg plus DEX 8 mg IV on day 1 of chemotherapy (1-day regimen, n=243); 2) the same regimen on the day 1 followed by DEX 8 mg orally on days 2 and 3 (3-day regimen, n=207); or PALO plus DEX plus aprepitant 125 mg on day 1 followed by aprepitant 80 mg on days 2 and 3 (triple regimen, n=104). The pre-specified primary endpoint was the proportion of patients with no DN (days 2-5 after the first cycle of chemotherapy). The two primary comparisons were 1-day vs. 3-day regimen, and triple vs. 3-day regimen, with statistical significance set to the 0.025 level. Results: The 1-day to 3-day regimen comparison was not statistically significant (44% vs. 47.8%; risk difference (RD) = -3.8%, 95% CI (-5.4 to 12.9%), P=0.421 (two-sided chi-square test). The triple to 3-day regimen comparison was also not significant (57.7% vs. 47.8%), RD= +9.9%, 95% CI (-1.9 to 21.3%), P=0.101. More patients receiving triple regimen experienced no acute-onset nausea compared with those administered only DEX (97.1% vs. 51.2%, P&lt;0.0001). Conclusions: This analysis provides evidence that PALO plus 1-day or 3-day DEX yield similar prevention of DN. The addition of aprepitant does not improve the control of DN. Complete results utilizing a multivariable model accounting for risk factors and trial heterogeneity will also be presented.

Efficacy of palonosetron-based antiemetic prophylaxis in breast cancer patients receiving anthracycline-containing adjuvant chemotherapy: A survey in 41 German gyneco-oncology practices.

e19540 Background: The emesis risk in young breast cancer (BC) patients (pts) receiving adjuvant anthracyclines (A) plus cyclophosphamide (C), taxanes or other cytotoxics is higher than anticipated earlier. Furthermore, antiemetic control seems to decline in subsequent cycles of chemotherapy (CT). The ASCO has classified AC to be highly emetogenic (HEC) in their antiemetic guidelines 2011. Palonosetron (P) is a 5-HT3-receptor-antagonist (5-HT3-RA) with higher receptor affinity and longer biological half-life than older compounds. Data suggest that Palonosetron is clinically more effective in the acute phase and that in contrast to the older 5-HT3-RA it is also effective in the delayed phase. P also showed to maintain its efficacy in subsequent cycles. Current antiemetic guidelines list palonosetron as preferred 5-HT3-RA in moderate emetogenic chemotherapy (MEC). Methods: To evaluate the efficacy of palonosetron after 4 cycles of A containing chemotherapy in BC patients, we have conducted a survey in 41 practices of the BNGO in Germany. Between Nov 2007 and Jan 2012 1299 patients have been documented. Median age was 55 years. Severity, frequency, duration and onset of N/V were recorded in a patient diary. Efficacy criteria were complete control CC (no V, no rescue, mild N); complete response (CR: no V, no rescue) and rescue medication. Results: At the beginning P was used as single agent (56%). Following the MASCC 2010 guidelines P was used in combination with dexamethasone (PDex, 15%) or plus dex and NK1-RA (PNDex, 23%), 16% of pts received additional medication. Efficacy after 4 cycles of CT: Overall (5 days): Complete control CC: (no V, no rescue, mild N) 63,3% of pts, complete response (CR: no V, no rescue) 73,7%; Rescue Medication was needed in 15,6% of pts. PDex CC 48,7%, CR 69,8 %, PNDex: CC 76,3%, CR % 83,33. N was also very well controlled: Overall (5 days) 56% of pts no nausea, 15% moderate N 3% severe N. Conclusions: Palonosetron in combination with dex and NK1-RA is very effective to control nausea and vomiting in A-based adjuvant chemotherapy in young breast cancer patients after 4 cycles of chemotherapy.

Palonosetron: An Evidence-Based Choice in Prevention of Nausea and Vomiting Induced by Moderately Emetogenic Chemotherapy

In 2003, the second-generation, 5-HT(3) receptor antagonist (5-HT(3) RA) palonosetron was approved by the FDA for the prevention of nausea and vomiting associated with highly and moderately emetogenic chemotherapy. We reviewed the current knowledge on the role of palonosetron against acute and delayed emesis in patients with solid tumors undergoing single-day moderately emetogenic chemotherapy regimens. A literature review in PubMed was performed to update currently available preclinical and clinical evidence on palonosetron, prioritizing randomized clinical trials. The distinct pharmacology of palonosetron provides a rationale behind the improved efficacy observed with the drug in prevention of delayed symptoms. This may be explained by allosteric binding properties and by palonosetron-triggered receptor internalization, which result in prolonged inhibition of the 5-HT(3) receptor function. Very recent pharmacology experiments have also suggested that palonosetron would be able to differentially inhibit 5-HT(3)/neurokinin 1 (NK-1) receptor signaling cross-talk. In two recent meta-analyses, palonosetron was shown to be more effective than other available 5-HT(3) RAs in preventing acute and delayed nausea and vomiting for both HEC and MEC. Recent findings also suggest that a single-day regimen of palonosetron plus dexamethasone (both drugs administered intravenously) may provide a reasonable therapeutic alternative to reduce the total dexamethasone dose administered in patients undergoing moderately emetogenic chemotherapy. On the basis of accumulating data, the evidence-based international guidelines devised from the major organizations have been recently updated to recommend the use of palonosetron plus 3-day dexamethasone for the optimal prevention of nausea and vomiting due to moderately emetogenic chemotherapy. There is still a need to investigate the efficacy of palonosetron in combination with an NK-1 receptor antagonist and dexamethasone in well-designed randomized trials.

The comparative study to evaluate the effect of palonosetron monotherapy versus palonosetron with dexamethasone combination therapy for prevention of postoperative nausea and vomiting

Background5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are effective and safe on postoperative nausea and vomiting (PONV). Palonosetron, the newest 5-HT3 antagonist, has potent antiemetic property. We hypothesized that a combination of palonosetron and dexamethasone could more decrease PONV than palonosetron alone.MethodsAmong the patients scheduled to undergo laparoscopic gynecologic surgery, mastoidectomy with tympanoplasty or thyroidectomy under general anesthesia, eighty four female patients with at least two PONV risk factors were enrolled in this study. They were received randomly 0.075 mg palonosetron and 4 mg dexamethasone (group C) or 0.075 mg palonosetron alone (group P). The severity of PONV using Rhodes index and the percentage of complete response during postoperative 24 hours were compared between groups.ResultsThe frequency of mild/moderate/great/severe PONV based on Rhodes index were 9.8%/0%/0%/0% and 9.3%/2.3%/2.3%/0% in group P and group C, respectively. Complete response for PONV was observed in 90.2% and 86% of patients in group P and group C, respectively. The overall incidence of PONV in group P and C was 9.8% and 14%, respectively. There was no significant difference between the two groups.ConclusionsThere were no differences between palonosetron monotherapy and combination therapy of palonosetron and dexamethasone in patients with high emetogenic risk.

Palonosetron and palonosetron plus dexamethasone to prevent postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy: A prospective, randomized, double-blind comparative study.

Background:Laparoscopic cholecystectomy (LC) is associated with a high risk of postoperative nausea and vomiting (PONV). Palonosetron is a newer 5HT3 receptor antagonist, which is routinely used in our institution to prevent PONV in patients scheduled for LC, under general anesthesia (GA). We formulated this study to find out whether the palonosetron and dexamethasone combination will be a better choice than palonosetron alone in the prevention of PONV.Materials and Methods:Sixty American Society of Anesthesiologists (ASA) physical status I and II patients, scheduled for LC under GA, were randomized to receive either palonosetron or a combination of palonosetron and dexamethasone. The number of complete responders (no emesis, no requirement of rescue anti-emetic medication) and the four-point nausea score was recorded at 2, 6, 24, 48 h postoperatively and the data was analyzed statistically.Results:The number of complete responders, as well as the nausea score, did not vary significantly (P=0.718) between the two groups over the 48-h postoperative period.Conclusions:The palonosetron and dexamethasone combination was not more effective than palonosetron alone in the prevention of PONV, in patients undergoing LC under GA.

Acute emesis: moderately emetogenic chemotherapy

This paper is a review of the recommendations for the prophylaxis of acute emesis induced by moderately emetogenic chemotherapy as concluded at the third Perugia Consensus Conference, which took place in June 2009. The review will focus on new studies appearing since the Second consensus conference in April 2004. The following issues will be addressed: dose and schedule of antiemetics, different groups of antiemetics such as corticosteroids, serotonin(3) receptor antagonists, dopamine(2) receptor antagonists, and neurokinin(1) receptor antagonists. Furthermore, antiemetic prophylaxis in patients receiving multiple cycles of moderately emetogenic chemotherapy will be reviewed. Consensus statements are given, including optimal dose and schedule of serotonin(3) receptor antagonists, dexamethasone, and neurokinin(1) receptor antagonists. The most significant recommendations (and changes since the 2004 version of the guidelines) are as follows: the best prophylaxis in patients receiving moderately emetogenic chemotherapy (not including a combination of an anthracycline plus cyclophosphamide) is the combination of palonosetron and dexamethasone on the day of chemotherapy, followed by dexamethasone on days2-3. In patients receiving a combination of an anthracycline plus cyclophosphamide, a combination of a serotonin(3) receptor antagonist plus dexamethasone, plus the neurokinin(1) receptor antagonist aprepitant on the day of chemotherapy, followed by aprepitant days2-3, is recommended.

Palonosetron in combination with 1-day versus 3-day dexamethasone for prevention of nausea and vomiting following moderately emetogenic chemotherapy: a randomized, multicenter, phase III trial

PurposeA phase III trial assessed the efficacy of palonosetron plus dexamethasone given once in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) following a broad range of moderately emetogenic chemotherapy (MEC) regimens.MethodsThis multicentre, randomized, open-label, non-inferiority trial evaluated two different treatment groups. One group received palonosetron (0.25 mg intravenously) and dexamethasone (8 mg intravenously) before chemotherapy, while the other was administered the same regimen on day 1 followed by dexamethasone 8 mg orally on days 2 and 3. The primary endpoint was complete response (CR; defined as no emetic episodes and no rescue medication) during the overall phase (days 1–5 after chemotherapy initiation). The non-inferiority margin was predefined as a 15% difference between groups in the primary endpoint.ResultsOf 332 chemotherapy-naïve patients included in the intention-to-treat analysis, 65.1% were female, and 35.2% received anthracycline plus cyclophosphamide (AC)-based regimens. Overall CR rates were 67.5% for those administered dexamethasone only on day 1 (n = 166), and 71.1% for those also administered dexamethasone on days 2 and 3 (n = 166; difference −3.6% (95% confidence interval, −13.5 to 6.3)). CR rates were not significantly different between groups during the acute (0–24 h post-chemotherapy; 88.6% versus 84.3%; P = 0.262) and delayed phases (days 2–5; 68.7% versus 77.7%; P = 0.116).ConclusionsPalonosetron plus single-dose dexamethasone administered before common MEC regimens provide protection against acute and delayed CINV which is non-inferior to that of palonosetron plus dexamethasone for 3 days. However, the major benefit of the single-day regimen occurs in patients receiving non-AC MEC regimens.

Palonosetron plus 3-day aprepitant and dexamethasone to prevent nausea and vomiting in patients receiving highly emetogenic chemotherapy

The combination of a neurokinin-1 receptor antagonist, dexamethasone, and a 5-HT(3) receptor antagonist is currently the standard antiemetic treatment in patients receiving cisplatin-based high emetogenic chemotherapy (HEC). The aim of this study was to evaluate the efficacy of a combination of palonosetron, a unique second-generation 5-HT(3) receptor antagonist, aprepitant, the only approved neurokinin-1 receptor antagonist, and dexamethasone as antiemetic prophylaxis in patients receiving HEC (cisplatin ≥50mg/mq). Chemotherapy-naïve adult patients, receiving cisplatin-based HEC, were treated with palonosetron 0.25mg/i.v., dexamethasone 20mg/i.v., and aprepitant 125mg/p.o., 1-h before chemotherapy. Aprepitant 80mg/p.o. and dexamethasone 4mg p.o. were administered on days 2-3. Primary end point was complete response (CR; no vomiting and no use of rescue medication), during the overall study period (0-120h). Secondary end points were complete control (CR and no more than mild nausea), emesis-free rate, and nausea-free rate during the acute (0-24h), delayed (24-120h), and overall (0-120h) periods. Safety was also evaluated. A total of 222 patients were included in the study. Median age was 62years, 76.6% were male and 23.4% female, and most common tumors were lung (66.7%) and head and neck (15.8%); 70.3% of patients achieved CR during the overall study period. Complete control, emesis-free rate, and nausea-free rate were 70.3%, 92.8%, and 59.9%, respectively, during the overall phase. The most commonly reported side effects were constipation (39% of patients) and headache (5%). This study shows that palonosetron in combination with aprepitant and dexamethasone is effective to prevent chemotherapy-induced nausea and vomiting in patients treated with cisplatin-based HEC.

Palonosetron for the prevention of chemotherapy-induced nausea and vomiting: approval and efficacy

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 characteristics (female gender, younger age, low alcohol consumption, history of motion sickness) are the major risk factors for CINV. This review provides a detailed description of palonosetron, a second-generation 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonist. The chemistry and pharmacology of palonosetron are described, as well as the initial and recent clinical trials. Palonosetron has a longer half-life and a higher binding affinity than the first-generation 5-HT(3) receptor antagonists. 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. In recent studies, compared to the first-generation 5-HT(3) receptor antagonists, palonosetron in combination with dexamethasone demonstrated better control of delayed CINV in patients receiving highly emetogenic chemotherapy. There were no clinically relevant adverse reactions reported in the palonosetron clinical trials which were different from the common reactions reported for the 5-HT(3) receptor antagonist class. Due to its efficacy in controlling both acute and delayed CINV, palonosetron may be very effective in the clinical setting of multiple-day chemotherapy and bone marrow transplantation.

Palonosetron: a second generation 5-hydroxytryptamine 3 receptor antagonist

Background: 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 characteristics (female gender, younger age, low alcohol consumption, history of motion sickness) are the major risk factors for CINV. Objective: This review provides a detailed description of palonosetron, a second generation 5-HT3 receptor antagonist. Methods: The chemistry and pharmacology of palonosetron are described, as well as the initial and recent clinical trials. Results/conclusion: Palonosetron has a longer half-life and a higher binding affinity than the first generation 5-HT3 receptor antagonists. 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. In recent studies, compared to the first generation 5-HT3 receptor antagonists, palonosetron in combination with dexamethasone demonstrated better control of delayed CINV in patients receiving highly emetogenic chemotherapy. There were no clinically relevant adverse reactions reported in the palonosetron clinical trials that were different from the common reactions reported for the 5-HT3 receptor antagonist class. Due to its efficacy in controlling both acute and delayed CINV, palonosetron may be very effective in the clinical setting of multiple-day chemotherapy and bone marrow transplantation.

A phase II dose-ranging study of palonosetron in Japanese patients receiving moderately emetogenic chemotherapy, including anthracycline and cyclophosphamide-based chemotherapy

BackgroundThe 5-HT3 receptor antagonists (RAs) help maintain the standard of care, in various combinations with other agents, for prevention of chemotherapy-induced nausea and vomiting (CINV). Palonosetron is a new generation 5-HT3 RA with indication not only acute but also delayed nausea and vomiting induced by moderately emetogenic chemotherapy (MEC). This study was carried out to determine the optimal dosage of palonosetron in combination with dexamethasone in patients in Japan. Patients and methodsThis study evaluated the efficacy and safety of palonosetron in patients receiving MEC combined with dexamethasone. Patients received single doses of 0.075, 0.25, or 0.75 mg of palonosetron before MEC. Dexamethasone was infused before palonosetron, at 20 mg for the patients receiving paclitaxel (Taxol) and 8 mg for the patients not receiving paclitaxel. The primary end point was complete response (CR: no emetic episodes and no rescue medication) in the acute phase (0–24 h). ResultsIn total, 204 patients (88 men, 116 women; 96 with paclitaxel, 108 without paclitaxel) were assessable for efficacy. No dose–response relationship was observed regarding the CR rate in the acute phase. CR rates increased dose dependently for delayed (24–120 h) and overall (0–120 h) phases in patients receiving anthracyclines and cyclophosphamide combination (AC/EC, n=80); however, the difference in CR rates among doses was not statistically significant. The most commonly reported adverse events related to palonosetron were constipation and headache, confirming the class safety profile. ConclusionThis study indicates a statistically nonsignificant trend for the dose–response relationship for antiemetic protection in the delayed and overall phases in AC/EC patients (the regimen currently considered to be more emetogenic than MEC).

Clinical Update on Palonosetron in the Management of Chemotherapy-Induced Nausea and Vomiting

The need to control chemotherapy-induced nausea and vomiting is continuously stimulating research to find better options for the optimal antiemetic care. Palonosetron is different from conventional serotonin receptor antagonists not only by the fact of having a longer half-life but also by higher binding affinity for serotonin receptors. It is the first agent in the class which is approved for preventing both delayed and acute emesis induced by moderately emetogenic chemotherapy. Recent studies using palonosetron-based antiemetic regimens, as well as in the clinical setting of multiple-day chemotherapy, have been reported. Palonosetron plus dexamethasone given as a pre-treatment infusion was effective for preventing acute and delayed emesis after moderately emetogenic chemotherapy. Palonosetron in combination with dexamethasone and aprepitant was highly effective in preventing emesis in the days following administration of moderately emetogenic chemotherapy. Treatment was well tolerated, with no unexpected adverse events. Multiple-day dosing of palonosetron plus dexamethasone was safe and effective for prevention of emesis induced by 5-day cisplatin-based chemotherapy. There was no evidence of cumulative toxicity when palonosetron was given three times over 5 days. Further evidence from ongoing clinical trials with palonosetron with or without dexamethasone will be available soon. Palonosetron represents an useful addition to the therapeutic armamentarium for the management of chemotherapy-induced nausea and vomiting. Further studies are needed to assess the effectiveness of palonosetron in combination with dexamethasone compared with that of older serotonin receptor antagonists combined with dexamethasone. However, palonosetron may offer advantages of convenience over the short-acting older antagonists due to its ability to be given as a single intravenous dose prior to chemotherapy.

Randomized, placebo‐controlled, pilot study evaluating aprepitant single dose plus palonosetron and dexamethasone for the prevention of acute and delayed chemotherapy‐induced nausea and vomiting

The combination of palonosetron and aprepitant is safe and effective in the prevention of chemotherapy-induced emesis (CIE). The purpose of this pilot study was to ascertain the effectiveness of 1-day versus 3-day aprepitant in the prevention of acute and delayed nausea and vomiting in patients who were receiving highly emetogenic chemotherapy. This study was institutional review board-approved and informed consent was obtained before this study was begun. This was a pilot, single-institution, randomized, double-blind, placebo-controlled trial that evaluated 3 different treatment arms. All groups received palonosetron 0.25 mg intravenously on Day 1 and dexamethasone on Days 1-4. Arm A received aprepitant 125 mg orally on Day 1 followed by 80 mg on Days 2-3. Arm B received aprepitant 125 mg orally on Day 1 and placebo on Days 2-3. Arm C received placebos on Days 1-3. The primary endpoint was to evaluate the proportion of patients with acute and delayed emesis within each group. Seventy-five patients were included in the analysis. The study commenced with 3 groups; however, an interim analysis displayed unacceptable emesis events in Arm C, and this group was terminated. There were no significant differences between Arms A and B for emesis, nausea, or the use of breakthrough antiemetics. In Arms A and B, 93% of patients were emesis-free from Days 1-5 compared with only 50% in Arm C. From this pilot study of patients who were receiving palonosetron, aprepitant, and dexamethasone for highly emetogenic chemotherapy, a single dose of aprepitant displayed similar effectiveness compared with 3-day aprepitant.

Pharmacokinetics of palonosetron in combination with aprepitant in healthy volunteers

ABSTRACTBackground: Palonosetron is a second-generation 5-HT3 receptor antagonist with a prolonged duration of action and higher receptor binding affinity than first-generation agents (ondansetron, granisetron, and dolasetron). Aprepitant is a selective antagonist of substance P/neurokinin 1 that augments the benefit of 5-HT3 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting.Methods: This randomized, open-label, two-way, crossover trial was designed to evaluate the effect of oral aprepitant on the pharmacokinetics and safety of a single intravenous (IV) dose of palonosetron in 12 healthy subjects. Treatment A consisted of a single IV bolus dose of palonosetron 0.25 mg on day 1. Treatment B added oral aprepitant 125 mg on day 1 (30 minutes prior to palonosetron) and 80 mg on days 2 and 3. Blood for pharmacokinetic evaluations was collected through 168 hours after palonosetron administration on days 1 and 15; safety was monitored through day 22.Results: Mean plasma concentration-time plots for palonosetron were virtually identical for palonosetron administered alone or with concomitant aprepitant. The ratio of geometric least-square mean values (with:without aprepitant) for Cmax was 98.6% (90% confidence interval [CI]: 61.8–157%), and for AUC0–∞ the ratio was 101% (90% CI: 85.6–119%). With and without aprepitant coadministration, respectively, mean plasma elimination half-life was 40 hours and 43 hours (difference: –3.0 hours; p = 0.348), mean total body clearance was 130 mL/min and 136 mL/min (difference: –5.6 mL/min; p = 0.735), and mean volume of distribution at steady-state was 410.9 L and 442.3 L (difference: –31.4 L; p = 0.463). Palonosetron alone and the palonosetron/aprepitant regimen were well tolerated.Conclusion: These results indicate no significant differences in pharmacokinetic parameters for palonosetron between the two treatments, and suggest that palonosetron can be safely coadministered with aprepitant with no alterations in the expected safety profile and no dosage adjustment necessary.