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Context No clinical trials have examined the effect of netupitant/palonosetron (NEPA) on chronic nausea in patients with cancer. Objectives In this pilot randomized trial, we assessed the efficacy of NEPA and placebo on chronic nausea. Methods This double-blind, parallel, randomized trial enrolled patients with cancer and chronic nausea for at least 1 month, intensity ≥4/10 and not on moderately or highly emetogenic systemic therapies. Patients started with a placebo run-in period from days 1 to 5; those without a placebo response proceeded to the double-blinded phase between days 6 to 15 (NEPA: placebo 2:1 ratio). The primary outcome was within-group change in average nausea over the 24 hours on a 0–10 numeric rating scale between day 5 and 15. Results Among the 53 enrolled patients, 46 proceeded to placebo run-in and 33 had blinded treatment (22 NEPA and 11 placebo). We observed a statistically significant within-group improvement in nausea numeric rating scale between day 5 and 15 in the NEPA group (mean change, −2.0; 95% CI, −3.1 to −0.8) and the placebo group (mean change, −2.3; 95% CI, −3.9 to −0.7). A complete response was achieved in 8 (38%) patients in the NEPA group and 2 (20%) in the placebo group by day 15. No grade 3–4 toxicities were attributed to NEPA. There were no statistically significant between-group differences for the primary/secondary outcomes. Conclusions NEPA and placebo were associated with similar magnitude of within-group improvement in chronic nausea without significant between-group differences (Clinicaltrials.gov NCT03040726).

Objectives Breast cancer (BC) patients represent a high-risk population for experiencing chemotherapy-induced nausea and vomiting (CINV), since they frequently receive highly emetogenic anthracycline-cyclophosphamide–based (AC) chemotherapy, and are often female and young, two predisposing risk factors for CINV. Guidelines recommend the combination of a neurokinin-1 receptor antagonist (NK1RA), 5-hydroxytryptamine-3 RA (5-HT3RA), and dexamethasone (DEX) for CINV prophylaxis in AC-treated patients. This post-hoc analysis evaluated the efficacy of NEPA, a fixed combination of netupitant (NETU [NK1RA]) and palonosetron (PALO [5-HT3RA]) in BC patients from two phase III studies. Methods Overall, 1460 BC patients received AC (Study 1) or non-AC (Study 2) therapy over 6060 cycles. Randomized patients received DEX with either NEPA or oral PALO (Study 1), or NEPA or aprepitant+oral PALO (Study 2) before chemotherapy. Results In AC-receiving patients, overall complete response (CR) rates with NEPA+DEX were statistically significantly higher than oral PALO+DEX rates (cycles 1–4: 73.9% vs 65.9%, 80.0% vs 66.0%, 83.6% vs 69.9%, 83.6% vs 74.4%, respectively). Overall, no significant nausea (NSN) rates were also superior with NEPA+DEX vs oral PALO+DEX (respectively, 74.2%–79.9% vs 68.5%–74.9%). A greater proportion of NEPA+DEX patients experienced “no-impact-on-daily-life” due to CINV (78.4% vs 71.4%) in cycle 1. In non-AC–receiving patients, prophylaxis with NEPA+DEX resulted in high CR and NSN rates across 1–4 chemotherapy cycles; no formal comparison with the control arm was performed. Conclusion NEPA+DEX administered as a single dose is an effective option for preventing CINV in BC patients receiving AC and non-AC, across multiple chemotherapy cycles. Clinical trials registration numbers Study 1: NCT01339260 , Study 2: NCT01376297 .

Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca2+)-dependent release of multiple neurotransmitters (dopamine, serotonin, substance P, etc.) from the gastrointestinal enterochromaffin cells and/or the brainstem. Intracellular Ca2+ signaling is triggered by activation of diverse emetic receptors (including tachykininergic NK1, serotonergic 5-HT3, dopaminergic D2, cholinergic M1, or histaminergic H1), whose activation in vomit-competent species can evoke emesis. Other emetogens such as cisplatin, rotavirus NSP4 protein and bacterial toxins can also induce intracellular Ca2+ elevation. Netupitant is a highly selective neurokinin NK1 receptor (NK1R) antagonist and palonosetron is a selective second-generation serotonin 5-HT3 receptor (5-HT3R) antagonist with a distinct pharmacological profile. An oral fixed combination of netupitant/palonosetron (NEPA; Akynzeo(®)) with >85% antiemetic efficacy is available for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Cannabinoid CB1 receptor agonists possess broad-spectrum antiemetic activity since they prevent vomiting caused by a variety of emetic stimuli including the chemotherapeutic agent cisplatin, 5-HT3R agonists, and D2R agonists. Our findings demonstrate that application of the L-type Ca2+ channel (LTCC) agonist FPL 64176 and the intracellular Ca2+ mobilizing agent thapsigargin (a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor) cause vomiting in the least shrew. On the other hand, blockade of LTCCs by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic efficacy against diverse agents that specifically activate emetogenic receptors such as 5-HT3, NK1, D2, and M1 receptors, but can also potentiate the antiemetic efficacy of palonosetron against the non-specific emetogen, cisplatin. In this review, we will provide an overview of Ca2+ involvement in the emetic process; discuss the relationship between Ca2+ signaling and the prevailing therapeutics in control of vomiting; highlight the evidence for Ca2+-signaling blockers/inhibitors in suppressing emetic behavior in the least shrew model of emesis as well as in the clinical setting; and also draw attention to the clinical benefits of Ca2+-signaling blockers/inhibitors in the treatment of nausea and vomiting.

This paper presents an overview of the efficacy of intravenous (IV) NEPA (fixed combination of the NK1RA, fosnetupitant, and 5-HT3RA, palonosetron) relative to oral NEPA and also to historical data for other NK1RA regimens. Data is compiled from 5 pivotal NEPA studies in adult chemotherapy-naive patients with solid tumors undergoing either cisplatin- or anthracycline cyclophosphamide (AC)-based chemotherapy. Additionally, data was reviewed from 10 pivotal Phase 3 studies utilizing other NK1RA regimens approved for clinical use. The overall (0-120 h) complete response (no emesis, no rescue use), no emesis, and no significant nausea rates for IV NEPA were similar to that of oral NEPA and were consistently numerically higher than historical NK1RA regimens. As a single-dose prophylactic antiemetic combination given with dexamethasone, IV NEPA is a highly effective and convenient guideline-compliant antiemetic agent which may offer a safety benefit over other IV NK1RA regimens due to its lack of associated hypersensitivity and injection-site reactions.

Despite the considerable progress achieved in the last 30 years, vomiting and, especially, nausea, continue to be two of the most distressing side-effects of cancer chemotherapy. In the late 1990s, several professional organisations published recommendations on the optimal antiemetic prophylaxis in patients submitted to chemotherapy and/or radiotherapy. The European Society of Medical Oncology (ESMO) and the Multinational Association of Supportive Care in Cancer (MASCC) published the results of the third Consensus Conference on antiemetics held in Perugia in June 2009 in Annals of Oncology in 2010 [1]. An update of these recommendations, including studies published from 1 January 2009 to 30 June 2015, was discussed in Copenhagen in June 2015 and is presented in this paper. The methodology for the guideline process is described in detail in the 2010 publication [1]. To change a 2010 recommendation or for a new guideline recommendation to be accepted, a consensus of at least 67% of the expert panellists was needed. As a general rule, the panel considered changes of 10% or greater to be sufficient to warrant the changing of a recommendation. Refereed/Peer-reviewed

A simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was firstly developed and validated for simultaneous determination of netupitant and palonosetron in human plasma using ibrutinib as the internal standard (IS). Following liquid-liquid extraction, the compounds were eluted isocratically on a Phenomenex C18 column (50mm×2.0mm, 3μm) with the mobile phase consisting of acetonitrile and 10mM ammonium acetate buffer (pH 9.0) (89:11, v/v) at the flow rate of 0.3mL/min. The monitored ion transitions were m/z 579.5→522.4 for netupitant, m/z 297.3→110.2 for palonosetron and m/z 441.2→138.1 for IS. Chromatographic run time was 2.5min per injection, which made it possible to analyze more than 300 of samples per day. The assay exhibited a linear dynamic range of 5-1000ng/mL for netupitant and 0.02-10ng/mL for palonosetron in plasma. The values for both within- and between-day precision and accuracy were well within the generally accepted criteria for analytical methods (15%). Selectivity, linearity, lower limit of quantification (LLOQ), accuracy, precision, stability, matrix effect, recovery and carry-over effect were evaluated for all analytes. The method is simple, rapid, and has been applied successfully to a pharmacokinetic study of netupitant and palonosetron in healthy volunteers.

Cytoplasmic calcium (Ca(2+)) mobilization has been proposed to be an important factor in the induction of emesis. The selective sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin, is known to deplete intracellular Ca(2+) stores, which consequently evokes extracellular Ca(2+) entry through cell membrane-associated channels, accompanied by a prominent rise in cytosolic Ca(2+). A pro-drug form of thapsigargin is currently under clinical trial as a targeted cancer chemotherapeutic. We envisioned that the intracellular effects of thapsigargin could cause emesis and planned to investigate its mechanisms of emetic action. Indeed, thapsigargin did induce vomiting in the least shrew in a dose-dependent and bell-shaped manner, with maximal efficacy (100%) at 0.5 mg/kg (i.p.). Thapsigargin (0.5 mg/kg) also caused increases in c-Fos immunoreactivity in the brainstem emetic nuclei including the area postrema (AP), nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMNX), as well as enhancement of substance P (SP) immunoreactivity in DMNX. In addition, thapsigargin (0.5 mg/kg, i.p.) led to vomit-associated and time-dependent increases in phosphorylation of Ca(2+)/calmodulin kinase IIα (CaMKIIα) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) in the brainstem. We then explored the suppressive potential of diverse chemicals against thapsigargin-evoked emesis including antagonists of: i) neurokinin-1 receptors (netupitant), ii) the type 3 serotonin receptors (palonosetron), iii) store-operated Ca(2+) entry (YM-58483), iv) L-type Ca(2+) channels (nifedipine), and v) SER Ca(2+)-release channels inositol trisphosphate (IP3Rs) (2-APB)-, and ryanodine (RyRs) (dantrolene)-receptors. In addition, the antiemetic potential of inhibitors of CaMKII (KN93) and ERK1/2 (PD98059) were investigated. All tested antagonists/blockers attenuated emetic parameters to varying degrees except palonosetron, however a combination of non-effective doses of netupitant and palonosetron exhibited additive antiemetic efficacy. A low-dose combination of nifedipine and 2-APB plus dantrolene mixture completely abolished thapsigargin-evoked vomiting, CaMKII-ERK1/2 activation and SP elevation. In addition, pretreatment with KN93 or PD98059 suppressed thapsigargin-induced increases in SP and ERK1/2 activation. Intracerebroventricular injection of netupitant suppressed vomiting caused by thapsigargin which suggests that the principal site of evoked emesis is the brainstem. In sum, this is the first study to demonstrate that thapsigargin causes vomiting via the activation of the Ca(2+)-CaMKII-ERK1/2 cascade, which is associated with an increase in the brainstem tissue content of SP, and the evoked emesis occurs through SP-induced activation of neurokinin-1 receptors.

Background NEPA is the first and only fixed oral combination of a long-acting NK1receptor antagonist (RA), netupitant, and a pharmacologically distinct 5-HT3RA, palonosetron. NEPA is approved for prevention of chemotherapy (ctx)-induced nausea and vomiting (CINV) in patients (pts) receiving cisplatin-based highly emetogenic ctx (HEC) or moderately emetogenic ctx (MEC). Here we present patient-reported outcomes (PRO) of patients (pts) receiving NEPA as an antiemetic prophylaxis during platin-based chemotherapy in a prospective non-interventional study. This group of patients presents a population at high risk for CINV. Methods The ongoing prospective AkyPRO study was designed to evaluate quality of life (QoL) in 2500 pts receiving NEPA for CINV prevention in single or two-day MEC or HEC over 3 cycles. The primary endpoint QoL was recorded by FLIE questionnaires. Secondary endpoints were efficacy, reported by pts and physicians on a 4-point scale; antiemetic rescue medication, and safety. Results In this interims analysis 595 pts receiving platin-based ctx were evaluated. PRO data show that ctx-induced vomiting can be controlled very efficiently in the majority of platin-receiving pts. Between 80-90% of pts reported no impact on daily life due to vomiting and between 84-90% of pts had a complete response (no vomiting, no rescue medication) in the 3 analysed cycles, independently of which type of platin-ctx they received. Furthermore, the majority of pts (74%, 81% and 68%, respectively) reported no or mild nausea in the cisplatin-, carboplatin- and oxaliplatin-subgroup in cycle 1. However, even mild nausea seems to have a strong impact on daily life with 40% of pts receiving cisplatin- or carboplatin-based chemotherapy and 46% of oxaliplatin-receiving pts reporting an impact on daily life due to nausea in cycle 1. Conclusions NEPA was proven highly effective in controlling both vomiting and nausea over three cycles of ctx independent of the type of platin administered. Despite the reported MEC classification of oxaliplatin in contrast to the HEC classification of cis- and carboplatin, nausea was more difficult to control in oxaliplatin-receiving patients. Legal entity responsible for the study Riemser Pharma. Funding Riemser Pharma. Disclosure M. Karthaus: Advisory / Consultancy: Helsinn; Advisory / Consultancy: Riemser. J. Schilling: Advisory / Consultancy: Riemser. All other authors have declared no conflicts of interest.

Many patients undergoing moderately or highly emetogenic chemotherapy experience chemotherapy-induced nausea/vomiting (CINV) and report reduced daily functioning, despite prophylaxis with antiemetic drugs. While modern antiemetics have largely alleviated acute emesis, management of nausea and delayed emesis remains particularly challenging. We briefly review the pathophysiologic mechanisms of CINV and the clinical impact of current antiemetics, i.e., the serotonin subtype 3 (5-HT3) receptor antagonists (RAs) and neurokinin-1 (NK1)RAs, before summarizing recent data from clinical trials of new agents. The new antiemetics reviewed include the two most recently approved drugs, the NK1RA rolapitant and the fixed-dose combination product, NEPA, which is composed of the NK1RA netupitant and the 5-HT3RA palonosetron. Phase 3 studies demonstrate improved control of CINV in the delayed and overall phases when rolapitant is added to a standard 5-HT3RA regimen. Phase 2 and phase 3 clinical trials with NEPA demonstrate improved control of CINV in the acute, delayed, and overall phases vs. 5-HT3RA regimens. These data suggest that delayed emesis can be substantially reduced via combined 5-HT3 and NK1 receptor neurotransmitter pathway inhibition.

Summary Background Highly emetogenic chemotherapy induces emesis in almost all patients in the absence of prophylaxis. Guidelines recommend use of a neurokinin-1 (NK-1) receptor antagonist in conjunction with a 5-HT 3 receptor antagonist and corticosteroid in patients receiving highly emetogenic chemotherapy. We aimed to assess rolapitant, an NK-1 receptor antagonist, for prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of cisplatin-based highly emetogenic chemotherapy. Methods We conducted two global, randomised, double-blind, active-controlled, phase 3 trials (HEC-1 and HEC-2) at 155 cancer centres (76 in HEC-1 and 79 in HEC-2) in 26 countries (17 in HEC-1 and 14 in HEC-2). We enrolled patients with cancer aged 18 years or older, who had not previously been treated with cisplatin, with a Karnofsky performance score of 60 or higher, and a predicted life expectancy of 4 months or longer. We used an interactive web-based randomisation system to randomly assign patients to treatment. Patients were stratified by sex and randomly allocated to either oral rolapitant (180 mg dose; rolapitant group) or a placebo that was identical in appearance (active control group) about 1–2 h before administration of highly emetogenic chemotherapy. All patients received granisetron (10 μg/kg intravenously) and dexamethasone (20 mg orally) on day 1, and dexamethasone (8 mg orally) twice daily on days 2–4. Every cycle was a minimum of 14 days. In up to five subsequent cycles, patients were allowed to receive the same study drug they were assigned in cycle 1, unless removed at the clinician's discretion. Patients could also choose to leave the study at any point. Efficacy analysis was done in the modified intention-to-treat population (comprising all patients who received at least one dose of study drug at a cancer centre compliant with Good Clinical Practice [GCP]). The primary endpoint was the proportion of patients achieving a complete response (no emesis or use of rescue medication) in the delayed phase (>24–120 h after initiation of chemotherapy) in cycle 1. These studies are registered with ClinicalTrials.gov, numbers NCT01499849 and NCT01500213. Both studies have been completed. Findings Between Feb 21, 2012, and March 12, 2014, 532 patients in HEC-1 and 555 patients in HEC-2 were randomly assigned to treatment. 526 patients in HEC-1 (264 rolapitant and 262 active control) and 544 in HEC-2 (271 rolapitant and 273 active control) received at least one dose of study drug at a GCP-compliant site and were included in the modified intention-to-treat population. A significantly greater proportion of patients in the rolapitant group had complete responses in the delayed phase than did patients in the active control group (HEC-1: 192 [73%] vs 153 [58%]; odds ratio 1·9, 95% CI 1·3–2·7; p=0·0006; HEC-2: 190 [70%] vs 169 [62%]; 1·4, 1·0–2·1; p=0·0426; pooled studies: 382 [71%] vs 322 [60%]; 1·6, 1·3–2·1; p=0·0001). The incidence of adverse events was similar across treatment groups. The most commonly reported treatment-related treatment-emergent adverse events in the rolapitant versus active control groups were headache (three [ vs two [ vs four [ vs three [ vs three [ vs 14 [5%]; HEC-2: 16 [6%] vs 14 [5%]), anaemia (HEC-1: one [ vs one [ vs two [ vs two [ vs two [ Interpretation Rolapitant in combination with a 5-HT 3 receptor antagonist and dexamethasone is well-tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the at-risk period (120 h) after administration of highly emetogenic cisplatin-based chemotherapy. Funding TESARO, Inc.

The prevention of chemotherapy-induced nausea and vomiting (CINV) has been revolutionized over the past 25 years. Guideline-based treatment means that vomiting can be prevented in the majority, but not in all patients. Therefore, antiemetic research continues with the goal of optimizing CINV control for all patients. This comprehensive review summarizes the research efforts in this field over the past few years. Emerging from this research are two new antiemetic agents, netupitant/palonosetron, the first antiemetic combination agent and rolapitant, a new NK1RA. In addition, studies have evaluated the benefits of olanzapine and ginger, explored optimal combinations of agents for delayed CINV prevention, confirmed that dexamethasone-sparing regimens are effective, and demonstrated the value of NK1RAs in high-dose chemotherapy settings as well as with certain moderately emetogenic chemotherapies such as carboplatin. Research has also validated the correlation between antiemetic guideline adherence and improved CINV control. Finally, regulatory authorities have utilized extreme caution in retiring some 5-HT3RAs or decreasing their maximum dose.

To better understand the anti-emetic profile of the 5-HT3 (palonosetron)- and the tachykinin NK1 (netupitant) -receptor antagonists, either alone or in combination, we evaluated the effects of palonosetron and/or netupitant pretreatment on cisplatin-evoked vomiting and changes in the phosphorylation of brainstem kinases such as the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), protein kinase C alpha/beta (PKCα/β), and protein kinase A (PKA) in the least shrew. Our results demonstrate that cisplatin (10mg/kg, i.p.) causes emesis in the least shrew over 40h with respective peak early- and delayed-phases occurring at 1 - 2 and 32 - 34h post-injection. During the early phase (0 - 16h post cisplatin), palonosetron (0.1mg/kg, s.c.) significantly protected shrews from vomiting with a near complete suppression of vomit frequency. Palonosetron also significantly protected shrews from vomiting during the delayed phase (27 - 40h post cisplatin), but the reduction in mean vomit frequency failed to achieve significance. On the other hand, netupitant (5mg/kg, i.p.) totally abolished vomiting during the delayed phase, and tended to suppress the mean vomit frequency during the acute phase. The combined treatment protected shrews almost completely from vomiting during both phases. Brainstem pERK1/2 levels were significantly elevated at all time-points except at 40h post-cisplatin administration. PKA phosphorylation tended to be elevated throughout the delayed phase, but a significant increase only occurred at 33h. Brainstem pPKCα/β levels were enhanced during acute-phase with a significant elevation at 2h. Palonosetron, netupitant or their combination had no effect on elevated pERK1/2 levels during acute phase, but the combination reversed ERK1/2 phosphorylation at 33h post-cisplatin treatment. In addition, only the combined regimen prevented the cisplatin-induced PKCα/β phosphorylation observed at the acute phase. On the other hand, palonosetron and netupitant, either alone or in combination, were effective in reducing the induced elevated pPKA levels during the delayed phase. These effects on cisplatin-related emetic signals downstream of 5-HT3- and NK1-receptors help us to better understand the intracellular basis of cisplatin-induced vomiting.

NEPA is an oral single, fixed-dose combination of netupitant, a new highly selective NK1 RA and palonosetron (PALO), a pharmacologically/clinically distinct 5-HT3 RA. It delivers antiemetic guideline-recommended prophylaxis by targeting two critical molecular pathways associated with chemotherapy-induced nausea/vomiting. This Phase III study demonstrated the superiority of NEPA compared with PALO., Background Antiemetic guidelines recommend co-administration of agents that target multiple molecular pathways involved in emesis to maximize prevention and control of chemotherapy-induced nausea and vomiting (CINV). NEPA is a new oral fixed-dose combination of 300 mg netupitant, a highly selective NK1 receptor antagonist (RA) and 0.50 mg palonosetron (PALO), a pharmacologically and clinically distinct 5-HT3 RA, which targets dual antiemetic pathways. Patients and methods This multinational, randomized, double-blind, parallel group phase III study (NCT01339260) in 1455 chemotherapy-naïve patients receiving moderately emetogenic (anthracycline–cyclophosphamide) chemotherapy evaluated the efficacy and safety of a single oral dose of NEPA versus a single oral dose (0.50 mg) of PALO. All patients also received oral dexamethasone (DEX) on day 1 only (12 mg in the NEPA arm and 20 mg in the PALO arm). The primary efficacy end point was complete response (CR: no emesis, no rescue medication) during the delayed (25–120 h) phase in cycle 1. Results The percentage of patients with CR during the delayed phase was significantly higher in the NEPA group compared with the PALO group (76.9% versus 69.5%; P = 0.001), as were the percentages in the overall (0–120 h) (74.3% versus 66.6%; P = 0.001) and acute (0–24 h) (88.4% versus 85.0%; P = 0.047) phases. NEPA was also superior to PALO during the delayed and overall phases for all secondary efficacy end points of no emesis, no significant nausea and complete protection (CR plus no significant nausea). NEPA was well tolerated with a similar safety profile as PALO. Conclusions NEPA plus a single dose of DEX was superior to PALO plus DEX in preventing CINV following moderately emetogenic chemotherapy in acute, delayed and overall phases of observation. As a fixed-dose antiemetic drug combination, NEPA along with a single dose of DEX on day 1 offers guideline-based prophylaxis with a convenient, single-day treatment.

This study was designed to determine the appropriate clinical dose of netupitant (NETU), a new NK1 receptor antagonist (RA), to combine with the 5-HT3 RA, palonosetron (PALO) in a fixed-dose antiemetic combination (NEPA). All NEPA doses provided superior prevention of chemotherapy-induced nausea and vomiting compared with PALO, with NEPA300 (300mg NETU + 0.50 mg PALO) being the best dose studied., Background NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK1) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-hydroxytryptamine type 3 (5-HT3) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program. Patients and methods This randomized, double-blind, parallel group study in 694 chemotherapy naïve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300 mg) + PALO 0.50 mg with oral PALO 0.50 mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1–4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0–120 h) phase. Results All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA100, NEPA200, and NEPA300, respectively versus 76.5% PALO; P < 0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0–24 h), delayed (25–120 h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable. Conclusions Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND.

Over the past decades major improvements in the management of chemotherapy induced nausea and vomiting (CINV) were obtained. With the correct use of antiemetic drugs, CINV can be prevented in almost 70%, and even up to, 80% of patients. Treatment guidelines enable physicians to integrate the latest clinical research into their daily practice. The large volume of rapidly evolving clinical data has been summarised and incorporated into treatment recommendations by well-known and reliable institutions. These organisations include the Multinational Association of Supportive Care in Cancer (MASCC), the European Society of Medical Oncology (ESMO), the American Society for Clinical Oncology (ASCO), and National Comprehensive Cancer Network (NCCN). However, despite the availability of these guidelines, there is an emerging evidence that adherence to, and implementation of, treatment recommendations is less than optimal. This review will especially focus on the content of the current antiemetic guidelines and will address the important question of how these guidelines are implemented in routine practice.

Nausea and vomiting are major side effects of chemotherapy and one key reason for non-compliance with cancer treatment. The introduction of 5-HT3 receptor antagonists in the 1990s was a major advance in the prevention of acute emesis, and highlighted the critical role of serotonin in the emetic response. The next major advance in the treatment of chemotherapy induced nausea and vomiting (CINV) occurred in 2003 with the introduction of aprepitant, a tachykinin 1 (NK1) receptor antagonist. Aprepitant not only reduced acute emesis but also helped in the reduction of delayed emesis. Also in 2003, palonosetron, a second generation 5-HT3 receptor antagonist became available. Unlike the first generation 5-HT3 receptor antagonists, palonosetron demonstrated efficacy in preventing both acute and delayed emesis. This review focuses on the mechanism of action of 5-HT3 and NK1 receptor antagonists in acute and delayed CINV prevention. We discuss first, the medicinal chemistry that led to the discovery of these antagonists to underline their common structural features. Second, we discuss their performance in the clinic and what it tells us about the emetic response. Finally, we present recent mechanistic studies that help provide a rationale for efficacy differences between palonosetron and other 5-HT3 receptor antagonists in the clinic. In vitro and in vivo experiments have shown that palonosetron can inhibit substance P-mediated responses, presumably through its unique interactions with the 5-HT3 receptor. The crossroads of acute and delayed emesis seem to include interactions among the 5-HT3 and NK1 receptor signaling pathways and inhibitions of these interactions could lead to improved treatment of CINV.

NEPA is the fixed combination antiemetic composed of the neurokinin-1 receptor antagonist netupitant and the 5-hydroxytryptamine-3 receptor antagonist palonosetron. The intravenous (i.v.) formulation of NEPA (fosnetupitant 235 mg/palonosetron 0.25 mg) was developed to enhance the convenience of NEPA administration. In a phase 3 study, i.v. NEPA showed acceptable safety with low risk for injection-site reactions. This study evaluated the pharmacokinetics and safety of i.v. NEPA in cancer patients. This was a single-center, single-dose phase 1 study in patients receiving highly emetogenic chemotherapy. Patients received a 30-min infusion of i.v. NEPA plus oral dexamethasone (12 mg) prior to chemotherapy, and oral dexamethasone (8 mg/daily) on days 2–4. Twenty-four patients received the complete i.v. NEPA infusion volume. Fosnetupitant maximum plasma concentration (Cmax) was reached at the end of infusion and decreased to Fosnetupitant conversion to netupitant occurred rapidly in cancer patients. Netupitant and palonosetron pharmacokinetic profiles in i.v. NEPA were similar to those reported for oral NEPA. i.v. NEPA was well tolerated with a similar safety profile to oral NEPA. i.v. NEPA provides additional administration convenience. Clinical trial registration number: EudraCT 2015-004750-18.

Background The oral, fixed-combination NEPA containing netupitant and palonosetron target crucial pathways involved in both acute and delayed chemotherapy-induced nausea and vomiting (CINV) in patients with highly emetogenic chemotherapy.Hematopoietic stem cell transplantation (HSCT) is associated with infectious complications, especially bloodstream infections (BSI). The risk factors associated with BSI include presence of indwelling vascular catheters. NEPA eliminates accessing intravenous catheters leading to a decreased risk of infection in HSCT recipients.There is a paucity of studies about the management of CINV during preparative regimens for HSCT. The aim of this study was to assess the safety of NEPA during and after HSCT conditioning. Methods Patients with chronic myeloid leukemia, multiple myeloma, myelodysplastic syndrome, and acute myeloid leukemia who received an allogeneic HSCT between 2017 and 2018 were retrospective studied. Conditioning regimen consisted of fludarabine and busulfan. Graft versus host disease prophylaxis was done with high-dose cyclophosphamide on days +3 to + 4 post-HSCT. Patients received a single capsule of NEPA prior to conditioning regimen and before cyclophosphamide, both with oral dexamethasone on days 1-3 . Safety was assessed by evaluation of adverse events and use of rescue medications (baclofen for hiccups and lactitol, macrogol and sennosides for constipation). Results Six patients were included: 4/6were male and median age was 50 years (IQR: 46-53 years). Two patients reported hiccups needing baclofen and 6 required rescue medications for constipation. Five out of six patients presented neutropenic enterocolitis on day +7, oral intake was stopped in 4 of them, total parenteral nutrition was started in 3 cases, 3 patients required extra antibiotic coverage, and 4 received analgesic therapy. All patients improved with conservative measures. Conclusions In this real-world observational study, the incidence of neutropenic enterocolitis was considerably higher than previous reports in HSCT recipients. It may be associated with NEPA administration but future studies will be needed to confirm this relationship. Legal entity responsible for the study Hospital Clinic Barcelona. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background The antiemetic standard of care recommended by guidelines for prevention of CINV in patients receiving cisplatin- and AC-based CT is the combination of an NK1 RA, a 5-HT3 RA, and dexamethasone (DEX). An IV formulation of NEPA (fixed combination of the NK1 RA, fosnetupitant and 5-HT3 RA, palonosetron) was recently approved in the US and is under review in Europe. Approval of IV NEPA was based on showing pharmacokinetic bioequivalence of IV fosnetupitant to oral netupitant and similar safety of IV NEPA to oral NEPA in a phase III study in patients receiving cisplatin-based CT. An IV/oral NEPA safety-controlled phase IIIb study was recently completed in patients receiving AC CT. In both studies, there were no injection-site or hypersensitivity reactions associated with IV NEPA. This secondary analysis presents the efficacy of IV NEPA relative to that of oral NEPA and other NK1 RAs in cisplatin and AC settings. Methods Data is compiled from 5 pivotal NEPA studies in a total of 2077 adult chemotherapy-naive patients with solid tumors undergoing either cisplatin- or AC-based CT. IV NEPA was administered as a single 30-min infusion; oral NEPA was given as a single capsule 60 min prior to CT. Patients also received DEX. Data was also reviewed from 9 phase III cisplatin and AC studies with other NK1 RA (aprepitant [APR], fosaprepitant [FOS], rolapitant [ROL]) regimens. No emesis rates are summarized for the overall phase (0-120h) of the initial cycle of CT. No formal statistical comparisons were performed. Results The overall no emesis rates of > 80% for IV NEPA were similar to oral NEPA in both cisplatin and AC settings and were favorable in the context of historical NK1 RA regimens. Table . 1765P Setting/Study IV NEPA + DEX Oral NEPA + DEX APR + 5-HT3RA + DEX FOS + 5-HT3RA + DEX ROL + 5-HT3RA + DEX Cisplatin Schwartzberg 2018 84.2% 88.6% - - Hesketh 2014 - 91.1% - - Zhang 2018 - 75.0% - - Grunberg 2011 - - 74.6% 72.9% Hesketh 2003 - - 77.7% - - Poli-Bigelli 2003 - - 66% - - Schmoll 2006 - - 76.5% - - Saito 2013 - - - 67.6% - Rapoport 2015 (HEC-1) - - - - 75% Rapoport 2015 (HEC-2) - - - - 71% AC Schwartzberg 2019 82.5% 86.1% - - - Aapro 2014 - 79.8% - - - Warr 2005 - - 76% - - Schwartzberg 2016 - - - - 72.4% Conclusions Both IV and oral formulations of NEPA along with DEX represent highly effective guideline-compliant single-dose antiemetics. Clinical trial identification NCT03403712. Editorial acknowledgement Jennifer Vanden Burgt, Minneapolis, MN, funded by Helsinn Healthcare, Lugano, Switzerland. Legal entity responsible for the study Helsinn Healthcare. Funding Helsinn Healthcare. Disclosure L. Schwartzberg: Advisory / Consultancy, Research grant / Funding (institution): Helsinn Healthcare ; Advisory / Consultancy, Research grant / Funding (institution): Tesaro; Advisory / Consultancy: Merck ; Advisory / Consultancy: Heron. M.S. Aapro: Advisory / Consultancy, Research grant / Funding (institution): Helsinn Healthcare; Advisory / Consultancy: Mundipharma; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Merck; Advisory / Consultancy: G1 Therapeutics.

The management of chemotherapy-induced nausea and vomiting (CINV) during preparative regimens for Hematopoietic Stem Cell Transplant (HSCT) continues to be a poorly studied area and an unmet patient need. The primary aim of this study was to assess the efficacy of NEPA to prevent N/V both during and after HSCT conditioning. NEPA is a recently approved combination antiemetic, containing fixed doses of netupitant and palonosetron. Nausea, emesis, and nutritional intake, were evaluated from the start of conditioning through day 4 post-transplant. NEPA was administered Days 1, 3 and 6 of conditioning, dexamethasone (Days 1-6) and BEAM (Carmustine (300 mg/m2 D1), Etoposide/Cytarabine (200/400 mg/m2 D2-5), Melphalan (140 mg/m2 D 6)) preparative regimen (Days 1-6) in 17 patients. Patient nausea and emesis was self-reported using daily assessments and rescue therapy was determined using chart review. Two out of 17 patients experienced emesis (11.7%) after all chemotherapy was completed with no emesis in any patient during chemotherapy. During the observation period, 6 patients did not receive rescue medications (35%) and time to first rescue in other patients was a mean of 188.9 hours from the start of chemotherapy (median 172.4, SD 89 hrs). Responses were classified as either complete (CR) or major (MR), with CR defined as: no emesis, mild-moderate nausea for hours 0-264 (6 days of chemotherapy and 5 days post-chemotherapy), and (MR) defined as: 1-2 emesis on only 1 day with any level nausea or no emesis with severe nausea. Five out of 16 patients reported CR (31%) and 11 reported a major response (69%) at their end of treatment (EOT) visit. One patient did not participate in the EOT visit. The patient population in this study was 47% female, 100% Caucasian, the average age was 62 years old and the following diagnoses were included: Peripheral T-cell Lymphoma (24%), Hodgkin lymphoma (23%), mantle cell lymphoma (29%), and Diffuse large B-cell lymphoma (24%). The following expected adverse events were reported amongst 17 treated patients: anemia (82%); neutropenia (65%); lymphocyte decrease (94%); decreased neutrophils (94%); white blood cell decrease (88%); abdominal pain (59%); constipation (53%); diarrhea (59%); abdominal cramping (35%); nausea (82% all grades); bacteremia (29%); hypophosphatemia (24%); and hypokalemia (29%). Constipation was deemed possibly related to NEPA; additional reported adverse events were not related to study drug. In this interim analysis, NEPA plus dexamethasone was effective in preventing emesis with BEAM conditioning with no increase in adverse events prior to HSCT.

Nausea and vomiting are among the most common and distressing consequences of cytotoxic chemotherapies. Nausea and vomiting can be acute (0-24h) or delayed (24-72 h) after chemotherapy administration. The introduction of 5-HT(3) receptor antagonists in the 90s was a major advance in the prevention of acute emesis. These receptor antagonists exhibited similar control on acute emesis but had no effect on delayed emesis. These findings led to the hypothesis that serotonin plays a central role in the mechanism of acute emesis but a lesser role in the pathogenesis of delayed emesis. In contrast, delayed emesis has been largely associated with the activation of neurokinin 1 (NK(1)) receptors by substance P. However, in 2003, a new 5-HT(3) receptor antagonist was introduced into the market; unlike first generation 5-HT(3) receptor antagonists, palonosetron was found to be effective in preventing both acute and delayed chemotherapy induced nausea and vomiting. Recent mechanistic studies have shown that palonosetron, in contrast to first generation receptor antagonists, exhibits allosteric binding to the 5-HT(3) receptor, positive cooperativity, persistent inhibition of receptor function after the drug is removed and triggers 5-HT(3) receptor internalization. Further, in vitro and in vivo experiments have shown that palonosetron can inhibit substance P-mediated responses, presumably through its unique interactions with the 5-HT(3) receptor. It appears that the crossroads of acute and delayed emeses include interactions among the 5-HT(3) and NK(1) receptor neurotransmitter pathways and that inhibitions of these interactions lend the possibility of improved treatment that encompasses both acute and delayed emeses.

Background The purpose of the study was to compare the effectiveness of olanzapine (OLN) and aprepitant (APR) for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy. Methods A phase III trial was performed in chemotherapy-naive patients receiving cisplatin ≥ 70 mg/m(2) or cyclophosphamide ≥ 500 mg/m(2) and doxorubicin ≥ 50 mg/m(2), comparing OLN to APR in combination with palonosetron (PAL) and dexamethasone (DEX). The OLN, PAL, DEX (OPD) regimen was 10 mg of oral OLN, 0.25 mg of IV PAL, and 20 mg of IV DEX prechemotherapy, day 1, and 10 mg/day of oral OLN alone on days 2-4 postchemotherapy. The APR, PAL, DEX (APD) regimen was 125 mg of oral APR, 0.25 mg of IV PAL, and 12 mg of IV DEX, day 1, and 80 mg of oral APR, days 2 and 3, and 4 mg of DEX BID, days 2-4. Two hundred fifty-one patients consented to the protocol and were randomized. Two hundred forty-one patients were evaluable. Results Complete response (CR) (no emesis, no rescue) was 97% for the acute period (24 hours postchemotherapy), 77% for the delayed period (days 2-5 postchemotherapy), and 77% for the overall period (0-120 hours) for 121 patients receiving the OPD regimen. CR was 87% for the acute period, 73% for the delayed period, and 73% for the overall period in 120 patients receiving the APD regimen. Patients without nausea (0, scale 0-10, MD Anderson Symptom Inventory) were OPD: 87% acute, 69% delayed, and 69% overall; APD: 87% acute, 38% delayed, and 38% overall. There were no grade 3 or 4 toxicities. CR and control of nausea in subsequent chemotherapy cycles were equal to or greater than cycle 1 for both regimens. OPD was comparable to APD in the control of CINV. Nausea was better controlled with OPD. Discussion In this study, OLN combined with a single dose of DEX and a single dose of PAL was very effective at controlling acute and delayed CINV in patients receiving highly emetogenic chemotherapy. CR rates were not significantly different from a similar group of patients receiving highly emetogenic chemotherapy and an antiemetic regimen consisting of APR, PAL, and DEX.

Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT(3)) antagonist and a corticosteroid. The neurokinin-1 (NK(1)) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT(3) antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK(1) antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT(3) antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK(1) antagonist occurred within the first 8-12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT(3) antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8-12 h following cisplatin-based chemotherapy, after which time substance P acting at NK(1) receptors becomes the dominant mediator of vomiting

Aim: As emesis is more difficult to suppress once it occurs, preventing chemotherapy-induced nausea and vomiting from the initial cycle through repeated cycles is essential for an optimal patient-centered approach to cancer management. NEPA is a novel, fixed-dose combination of a new NK1 receptor antagonist (RA), netupitant (NETU 300 mg), and palonosetron (PALO 0.50 mg), a pharmacologically distinct 5-HT3 RA. NEPA is designed to overcome barriers hindering guideline adherence by targeting two molecular pathways with a single, oral fixed-dose product. NEPA was previously shown to be superior to PALO after a single chemotherapy (CT) cycle; maintenance of efficacy over multiple cycles has been evaluated in a combined dataset from 2 pivotal trials. Methods: These large multinational, randomized studies assessed the efficacy/safety of a single oral dose of NEPA (vs PALO or aprepitant+PALO) in chemotherapy-naive patients receiving multiple cycles of either anthracycline-based (AC) moderately emetogenic CT (MEC) [study 1] or non-AC based MEC or highly emetogenic CT (HEC) [study 2]. All patients also received oral dexamethasone (DEX). Efficacy endpoints were complete response (CR: no emesis, no rescue) and no significant nausea (max Results: 1033 NEPA-treated patients participated in 4428 total cycles in these two trials; 76% completed at least 4 cycles. Overall CR and no significant nausea rates were high and were maintained across 4 cycles of CT with rates being modestly lower in patients receiving AC MEC compared to non-AC MEC and HEC. CR No Significant Nausea (N=AC/non-AC/HEC) AC MEC Non-AC MEC HEC AC MEC Non-AC MEC HEC Cycle 1 (N=724/235/74) 74% 80% 84% 75% 85% 82% Cycle 2 (N=635/212/68) 80% 88% 79% 77% 87% 87% Cycle 3 (N=598/196/63) 84% 91% 91% 78% 89% 92% Cycle 4 (N=551/181/52) 84% 92% 85% 80% 94% 85% The type/incidence of AEs was typical for a diverse cancer population receiving chemotherapy and raised no safety concerns. Conclusions: This is the largest multiple cycle dataset for an antiemetic and provides confidence in the preservation of benefit with NEPA over multiple cycles of AC- and non-AC MEC and HEC. NEPA, a highly convenient, guideline-based antiemetic combination may result in greater adherence and consequently improved emetic control. Disclosure: M.S. Aapro: Consultant, Research Funding, Honoraria: Helsinn Healthcare; R. Gralla: Consultant: Helsinn Healthcare and Eisai Inc.; M. Karthaus: Consultant: Helsinn Healthcare; L. Schwartzberg: Consultant: Helsinn Healthcare & Eisai Inc.; G. Rossi: Employee: Helsinn Healthcare; G. Rizzi: Employee: Helsinn Healthcare; M.E. Borroni: Employee: Helsinn Healthcare; M. Palmas: Employee: Helsinn Heathcare; H.S. Rugo: Consultant and Research Funding: Helsinn Healthcare; K. Jordan: Consultant and Honoraria: Helsinn Healthcare, Merck.

Aim: Female gender and young age are well-established patient-related risk factors increasing the emetogenic potential of chemotherapy. NEPA, a novel fixed-dose combination of the new NK1 receptor antagonist (RA), netupitant (NETU) and the pharmacologically distinct 5-HT3 RA, palonosetron (PALO) was superior to PALO in pivotal studies. The intent of this analysis was to evaluate the effect of gender and age on treatment response. Methods: Data was combined from 3 pivotal studies in chemotherapy-naive patients with solid tumors undergoing cisplatin-based HEC. Patients received either NEPA (100/200/300 mg oral NETU+0.50 mg oral PALO) (studies 1 & 2) or 0.50 mg oral PALO (studies 1 & 3). All patients also received dexamethasone (DEX) on days 1-4. Overall (0-120h) complete response (CR: no emesis, no rescue medication) rates were calculated for females and males Results: In both treatment groups, CR rates were lower in all females (69% PALO, 82% NEPA) and those PALO NEPA % Difference (95% CI) Females 69.0% 80.0% 11.0 (-1.0;23.0) Females≥55 (moderate risk) (N=108/103) 69.4% 84.5% 15.0 (3.9;26.2) Males 71.4% 89.7% 18.3 (7.6;29.0) Males≥55 (lowest risk) (N=206/153) 81.1% 92.8% 11.7 (5.0;18.5) Conclusions: NEPA resulted in a consistent and similar magnitude of benefit for both younger and older patients, both genders, and for all combined gender/age risk groups. Younger women remain the most at risk for emesis, but the NEPA fixed-dose combination+DEX offers a clear advantage over PALO+DEX for this group as well. Disclosure: P. Hesketh: Non-compensated consultant for Helsinn Healthcare; K. Jordan: Speakers bureau for Merck and Helsinn Healthcare; Advisor for Helsinn Healthcare; R. Gralla: Advisor for Helsinn Healthcare, Merck, and Eisai

Introduction Nausea and emesis are significant adverse events of chemotherapy. Substance P plays a major role in the emetic process especially in the delayed emesis occurring 24h after treatment and beyond. Antagonism of substance P effect at the neurokinin 1 (NK1) receptor level is a validated target in showing a broad antiemetic activity in animal models of emesis and also in humans. Within the new NK1 antagonists in clinical trials, Netupitant (Netu) has been characterized as an antiemetic in vitro and in vivo in various pharmacological experiments against emesis induced by chemotherapeutics. In vitro studies have shown that the CYP3A4 isoenzyme is the major enzyme involved in the oxidative metabolism of Netu. Methods The in vitro inhibition potential of Netu and its major metabolites M1 and M2 has been studied for the human cytochrome P450 isoenzymes CYP1A2, 2C9, 2C19, 2D6 and 3A4 utilizing human liver microsomes and isoform selective substrates. Results Netu inhibited the CYP3A4-dependent metabolism of the two isoform selective probe-substrates midazolam and testosterone with estimated IC50 (±S.E.) values of 5.9 ± 1 and 1.7 ± 0.2 µM, respectively. For the hydroxylation of diclofenac, catalyzed by CYP2C9, IC50 (±S.E.) of 18.0 ± 6 and 22.6 ± 3 µM were calculated in two different experiments, utilizing both the free base, and the Netu hydrochloride as inhibitors. Netu showed no significant inhibition potential for CYP1A2, 2C19 and 2D6 (IC50s >100 µM). Conclusions Significant metabolic drug-drug interactions in human are not anticipated for compounds metabolized mainly by CYP1A2, 2C19 and 2D6 and are very unlikely for CYP2C9 metabolized drugs based on the expected human plasma concentration of Netu in the low μmolar range. However, metabolic drug-drug interactions are possible for co-medicated drugs metabolized mainly by CYP3A4, based on the high in vitro affinity of Netu for this isoenzyme, as tested with testosterone and midazolam (app Ki ∼ 1.1 to 2.2 µM) and for the inhibition potential of the metabolites M1 and M2 similar to the parent compound. The in vivo CYP3A4 interaction has been studied in appropriate designed clinical interaction studies. Disclosure C. Giuliano: Helsinn healthcare employee, E. Lovati: Helsinn Healthcare employee, C. Funk: Roche employee, M. Potthast: Roche employee, C. Pietra: Helsinn employee.

Background Netupitant (NETU) is a highly selective neurokinin 1 receptor antagonist developed to provide protection from nausea and vomiting induced by emetogenic chemotherapy. The objectives of the study were to investigate the pharmacokinetic (PK) profile, the mass balance recovery, the excretion pathways and the metabolism of [14C]NETU in an open-label study in 6 healthy male subjects receiving a single-nominal-dose of 300 mg as oral suspension. Methods Plasma, urine and feces samples were collected up to 336h after dosing, plus two additional 24h excreta collections until 696h. Total radioactivity was measured by liquid scintillation counting (liquid samples) and after combustion in oxygen (non-liquid samples). PK parameters for NETU and its metabolites were analyzed by liquid chromatography-tandem mass spectrometry. Results [14C]-NETU is rapidly absorbed with peak in plasma concentration ranging between 2h and 5.5h post dose. Elimination is mainly via the feces, with approximately 71% of the total radioactivity recovered at 696h. Urinary elimination accounts for less than 4% of total radioactivity. Cumulative percent of total radioactivity suggests that approximately half of the administered dose was recovered within 120h and, based on an extrapolation, elimination was completed by 696h. NETU undergoes extensive metabolism forming phase I and II metabolites. The main metabolites of NETU are M1 (N-demethylated NETU), M2 (NETU N-oxide) and M3 (monohydroxy NETU) which, on average, account respectively for 29%, 14% and 33% of the NETU plasma exposure. Phase I metabolites observed include those formed through N-demethylation, mono and di-hydroxylation, N-oxidation, desaturation, N-formylation, oxidation and reduction to a keto group and oxidation to an acid. Phase II metabolites include those formed by glucuronidation and conjugation to a hexose group. Conclusions These data indicate that the hepatic/biliary route, rather than renal clearance is the major elimination route for drug-related entities. NETU undergoes extensive metabolism via phase I and II metabolic reactions with M1, M2 and M3 as the main circulating metabolites. NETU was well tolerated. Disclosure C. Giuliano: Helsinn employee, S. Calcagnile: Helsinn employee, All other authors have declared no conflicts of interest.