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Simple Summary: Based on the predicament of the scarcity of clinical drugs for breast cancer and the potential of targeting AGK in the treatment of breast cancer, this study employed a structure-based drug screening strategy that integrates in vitro cell lines and subcutaneous tumor models in nude mice to identify potential marketed drugs targeting AGK, with the aim of providing survival benefits for breast cancer patients. Background: Currently, there is a significant lack of effective pharmacological agents for the treatment of breast cancer. Acylglycerol Kinase (AGK), a lipid kinase, has been found to be aberrantly expressed in breast cancer and is closely associated with tumor proliferation, migration, and invasion. However, no clinical anti-tumor drugs specifically targeting this kinase have been developed. Methods: siRNA was utilized to knock down the AGK gene; CCK8 and colony formation assays were employed to evaluate the in vitro proliferative capacity of tumor cells. Molecular dynamics simulations and BIL assays were conducted to analyze drug binding affinity. Annexin V/PI staining was used to assess apoptotic phenomena; subcutaneous xenograft tumor experiments in nude mice were performed to confirm the in vivo anti-tumor efficacy of the drug. Results: Netupitant exhibited stable binding affinity for AGK and interacted with amino acids within the ATP-binding region of the enzyme. The IC50 values for the SK-BR-3 and MDA-MB-231 cell lines were determined as 16.15 ± 4.25 µmol/L and 24.02 ± 4.19 µmol/L, respectively; at a concentration of 2.5 µmol/L, Netupitant effectively inhibited clonogenic capacity in breast cancer cells; furthermore, treatment with 10 µmol/L significantly induced apoptosis in these cells. Doses of 50 mg/kg and 100 mg/kg Netupitant markedly suppressed growth rates of subcutaneous xenograft tumors in nude mice while also promoting apoptotic processes. Both in vivo and in vitro studies indicated that Netupitant could inhibit the activation of the PI3K/AKT/mTOR signaling pathway. Conclusions: By targeting AGK, Netupitant inhibits its kinase activity, which leads to reduced phosphorylation levels of PTEN, thereby suppressing the activation of the PI3K/AKT/mTOR signaling pathway and ultimately resulting in apoptosis in breast cancer cells. [ABSTRACT FROM AUTHOR]

Despite the widespread use of immuno-oncological and targeted therapy in the treatment of malignant tumors, in real clinical practice the role of chemotherapy is still significant, used both in mono regimen and in combination with other antitumor drugs. Cytostatics cause a wide range of adverse events, which are often the cause of dose reduction, cyclical disorders, or even discontinuation of therapy. One of the most common symptoms is chemotherapy-induced nausea and vomiting which affect not only the quality of life, but also the results of treatment. It is important to address these issues from prevention and treatment perspectives so that patients remain committed to their treatment regimens. Since nausea and vomiting induced by chemotherapy are classified into 5 different types, the main medications for prevention and treatment include 5-hydroxytryptamine type 3 (5-HT3) and neurokinin-1 (NK1) receptor antagonists and corticosteroids. Simultaneous use of drugs from the groups of second-generation NK1 receptor blockers and 5-HT3 receptor blockers, for example: netupitant + palonosetron in combination with corticosteroids, makes it possible to achieve maximum antiemetic effect, even with the most emetogenic antitumor treatment regimens.

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma, for which cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab(R–CHOP) is one of the standard regimens. Given that R–CHOP is highly emetogenic, chemotherapy-induced nausea and vomiting (CINV) prevention is clinically important. However, there is a paucity of studies focusing on these patients. This study aimed to ascertain the effectiveness of an oral fixed-dose combination of netupitant and palonosetron (NEPA) in preventing CINV in patients with DLBCL undergoing first-line R-CHOP chemotherapy. Seventy patients were enrolled in this single-center prospective non-comparative study conducted between November 2020 and May 2023 in South Korea. NEPA was administered 1 h prior to chemotherapy initiation on day 1. The primary endpoint of the study was the complete response rate (no emesis, and no rescue medication) during the acute, delayed, and overall phases, which were assessed over a period of 120 h post-chemotherapy. The complete response rates for NEPA were 90.0% [95% CI 80.5, 95.9] for the acute phase, 85.7% [95% CI 75.3, 92.9] for the delayed phase, and 84.3% [95% CI 73.6, 91.9] for the overall phase, with no-emesis rates (acute: 97.1% [95% CI 97.1, 99.7], delayed: 95.7% [95% CI 88.0, 99.1], overall: 92.9% [95% CI 84.1, 97.6]). NEPA was well tolerated with no severe treatment-emergent adverse events. NEPA exhibited substantial efficacy in mitigating CINV in DLBCL patients undergoing R–CHOP chemotherapy, demonstrating high CR and no-emesis rates, and favorable safety profiles.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma, for which cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab(R–CHOP) is one of the standard regimens. Given that R–CHOP is highly emetogenic, chemotherapy-induced nausea and vomiting (CINV) prevention is clinically important. However, there is a paucity of studies focusing on these patients. This study aimed to ascertain the effectiveness of an oral fixed-dose combination of netupitant and palonosetron (NEPA) in preventing CINV in patients with DLBCL undergoing first-line R-CHOP chemotherapy. Seventy patients were enrolled in this single-center prospective non-comparative study conducted between November 2020 and May 2023 in South Korea. NEPA was administered 1 h prior to chemotherapy initiation on day 1. The primary endpoint of the study was the complete response rate (no emesis, and no rescue medication) during the acute, delayed, and overall phases, which were assessed over a period of 120 h post-chemotherapy. The complete response rates for NEPA were 90.0% [95% CI 80.5, 95.9] for the acute phase, 85.7% [95% CI 75.3, 92.9] for the delayed phase, and 84.3% [95% CI 73.6, 91.9] for the overall phase, with no-emesis rates (acute: 97.1% [95% CI 97.1, 99.7], delayed: 95.7% [95% CI 88.0, 99.1], overall: 92.9% [95% CI 84.1, 97.6]). NEPA was well tolerated with no severe treatment-emergent adverse events. NEPA exhibited substantial efficacy in mitigating CINV in DLBCL patients undergoing R–CHOP chemotherapy, demonstrating high CR and no-emesis rates, and favorable safety profiles. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced nausea and vomiting is a common problem during cancer treatment, especially in breast cancer patients with anthracycline/cyclophosphamide (ас) chemotherapy. Netupitant/palonosetron (NEPA; Akynzeo®) is a fixed-dose combination of two drugs (netupitant, a neurokinin 1 receptor antagonist; and palonosetron, a serotonin 3 receptor antagonist) which target two diferent signalling pathways involved in the induction of vomiting. Approved for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting in adults, netupitant/palonosetron is given orally or via intravenous infusion as a single dose prior to chemotherapy. In clinical trials, high proportions of patients who received netupitant/palonosetron (used in combination with the corticosteroid dexamethasone) prior to chemotherapy reported no vomiting, no requirement for rescue medication, and no signifcant nausea in the 5 days post chemotherapy. Both the oral and intravenous formulations of the drug combination are well tolerated. Thus, netupitant/palonosetron is a simple, convenient and efective drug combination for the prevention of acute and delayed xhemotherapy-induced nausea and vomiting in patients receiving chemotherapy that has a moderate to high emetogenic potential.

Abstract Introduction Non‐inferiority of NEPA (fixed combination of NK1 receptor antagonist (RA), netupitant, and 5‐HT3RA, palonosetron) versus an aprepitant regimen was previously shown in a pragmatic study in patients receiving anthracycline cyclophosphamide (AC) and non‐AC moderately emetogenic chemotherapy (MEC). In the MEC group a numerically higher complete response (CR: no emesis, no rescue) rate was seen for NEPA during the overall 0–120 h phase (NEPA 76.1% vs. 63.1% aprepitant). As NEPA exhibits long‐lasting efficacy, this study evaluated a prolonged period up to 144 h, beyond the traditional 120 h post‐chemotherapy. In this post‐hoc analysis we explore the comparative efficacy of NEPA versus the aprepitant regimen in the MEC group up to 144 h, while also assessing the impact of risk factors on CINV prevention. Methods This was a pragmatic, multicenter, randomized, prospective study. Oral NEPA was administered as a single dose on day 1, while aprepitant was given on days 1–3 + ondansetron on day 1; all patients were to receive dexamethasone on days 1–4. Patients were chemotherapy‐naïve and receiving MEC, with a subset evaluation of those with a risk factor for developing CINV (i.e., female, male

Many patients with various localizations of malignant neoplasms require therapy aimed at preventing or reducing the manifestations of nausea and vomiting induced by anticancer pharmacotherapy. New drugs to prevent the development of complications of chemotherapy are critical to improve the quality of life of patients and their adherence to therapy. Palonosetron, a new generation 5-HT3 receptor antagonist, has a long half-life (up to 40 hours) and a 30-fold higher affinity for 5-HT3 receptors compared to previous generations of 5-HT3 receptor antagonists. Clinical studies have shown the ability of palonosetron in combination with dexamethasone and, if indicated, neurokinin antagonists to effectively prevent the development of nausea and vomiting during single- and multi-day cycles of chemotherapy for both solid tumors and hematological diseases, including high-dose chemotherapy, in preparation for transplantation of auto- and allogeneic stem cells. The innovative oral drug Akynzeo is currently available for use in clinical practice, which includes 2 highly selective NK1 and 5-HT3 receptor antagonists in fixed doses. The drug prevents induced nausea and vomiting during moderate and highly emetogenic chemotherapy in more than 90 % of cases, both in the acute and delayed phases.

Introduction: Non‐inferiority of NEPA (fixed combination of NK1 receptor antagonist (RA), netupitant, and 5‐HT3RA, palonosetron) versus an aprepitant regimen was previously shown in a pragmatic study in patients receiving anthracycline cyclophosphamide (AC) and non‐AC moderately emetogenic chemotherapy (MEC). In the MEC group a numerically higher complete response (CR: no emesis, no rescue) rate was seen for NEPA during the overall 0–120 h phase (NEPA 76.1% vs. 63.1% aprepitant). As NEPA exhibits long‐lasting efficacy, this study evaluated a prolonged period up to 144 h, beyond the traditional 120 h post‐chemotherapy. In this post‐hoc analysis we explore the comparative efficacy of NEPA versus the aprepitant regimen in the MEC group up to 144 h, while also assessing the impact of risk factors on CINV prevention. Methods: This was a pragmatic, multicenter, randomized, prospective study. Oral NEPA was administered as a single dose on day 1, while aprepitant was given on days 1–3 + ondansetron on day 1; all patients were to receive dexamethasone on days 1–4. Patients were chemotherapy‐naïve and receiving MEC, with a subset evaluation of those with a risk factor for developing CINV (i.e., female, male <60 years, male ≥60 years who received carboplatin, or male ≥60 years with anxiety). CR rates were compared during the extended overall (0–144 h) phase. Results: The MEC group included 211 patients; of these 181 were in the risk factor subset. Significantly higher CR rates were seen for NEPA than aprepitant during the extended overall phase for the total MEC group (NEPA 77.1%, aprepitant 57.8%, p = 0.003) and also in the subset of patients with CINV risk factors (NEPA 73.9%, aprepitant 56.2%, p = 0.012). Conclusion: A single dose of NEPA, administered on day 1 only, was more effective than a 3‐day aprepitant regimen in preventing CINV for an extended duration in patients receiving MEC and in those with emetic risk factors. [ABSTRACT FROM AUTHOR]

AimTo assess the efficacy of oral NEPA (netupitant-palonosetron 300/0.50 mg) over multiple chemotherapy cycles.MethodsTwo randomized phase III studies evaluated a single dose of oral NEPA given on day 1 in chemotherapy-naive patients receiving anthracycline-cyclophosphamide (AC)-based (Study 1) or highly (HEC)/moderately (MEC) emetogenic chemotherapy (safety Study 2). Oral NEPA was compared with oral palonosetron 0.50 mg (Study 1) or oral aprepitant 125 mg day 1, 80 mg days 2-3/palonosetron 0.50 mg (Study 2; no formal statistical comparisons). Oral dexamethasone was administered in all treatment groups. Complete response (CR; no emesis/no rescue medication), no emesis, and no significant nausea (NSN) rates during acute (0-24 h) and delayed (>24-120 h) phases of chemotherapy cycles 1-4 in each study were evaluated.ResultsIn Study 1, 1450 patients received 5969 chemotherapy cycles; in Study 2, 412 patients received 1961 chemotherapy cycles. In each study, ≥75% of patients completed 4 or more cycles. In Study 1, oral NEPA was superior to palonosetron in preventing chemotherapy-induced nausea and vomiting (CINV) in the acute and delayed phases of cycle 1, with higher rates of CR (all P

Aim: Despite numerous available antiemetics, chemotherapy induced nausea and vomiting (CINV) still affects many patients, and CINV related hospitalizations and costs often result. Materials & methods: PrecisionQ analyzed its database to evaluate CINV related hospitalizations and costs following antiemetics use including netupitant/fosnetupitant with palonosetron (NEPA), aprepitant/fosaprepitant with ondansetron (APON) or aprepitant/fosaprepitant with palonosetron (APPA) in patients receiving highly emetogenic chemotherapy or moderately emetogenic chemotherapy. Results: Database analysis identified 15,583 patient records (807 NEPA, 2023 APON, 12,753 APPA) and mean CINV related hospitalization costs were lower across all patients receiving NEPA (US$301) compared with patients receiving APON ($1006, p < 0.0001) or APPA ($321, p < 0.0001). Conclusion: NEPA is associated with lower CINV related hospitalization costs compared with APON and APPA among patients receiving highly emetogenic chemotherapy or moderately emetogenic chemotherapy. Chemotherapy patients often experience nausea and vomiting that not only has a negative impact on the patient's quality of life but can also result in unplanned hospitalizations with high associated costs. Numerous medications and specific guidelines are available to prevent nausea and vomiting in patients with cancer. Specifically, the combination of two classes of medications (serotonin inhibitors + neurokinin type 1 inhibitors) has been shown to provide the greatest benefit. However, hospitalizations due to nausea and vomiting still occur, and providers require further information to determine the best options for their patients. In this study, the combination of netupitant/fosnetupitant with palonosetron resulted in lower hospitalization costs compared with aprepitant/fosaprepitant with ondansetron or aprepitant/fosaprepitant with palonosetron in chemotherapy patients. Netupitant or fosnetupitant with palonosetron result in lower chemotherapy induced nausea and vomiting related hospitalization costs compared with aprepitant or fosaprepitant-based regimens. [ABSTRACT FROM AUTHOR]

Considering the frequent use of netupitant in polytherapy, the elucidation of its oxidative metabolization pattern is of major importance. However, there is a lack of published research on the redox behavior of this novel neurokinin-1 receptor antagonist. Therefore, this study was performed to simulate the intensive hepatic biotransformation of netupitant using an electrochemically driven method. Most of the known enzyme-mediated reactions occurring in the liver (i.e., N-dealkylation, hydroxylation, and N-oxidation) were successfully mimicked by the electrolytic cell using a boron-doped diamond working electrode. The products were separated by reversed-phase high-performance liquid chromatography and identified by high-resolution mass spectrometry. Aside from its ability to pinpoint formerly unknown metabolites that could be responsible for the known side effects of netupitant or connected with any new perspective concerning future therapeutic indications, this electrochemical process also represents a facile alternative for the synthesis of oxidation products for further in vitro and in vivo studies.

Objective: Chemotherapy-induced nausea and vomiting (CINV) are common with doxorubicin-cyclophosphamide (AC) chemotherapy. Recommended antiemetic regimens incorporate neurokinin-1 receptor antagonist (NK1RA), 5-hydroxytryptamine type-3 receptor antagonist (5HT3RA), corticosteroid, and dopamine antagonists. This post-hoc analysis compared results of 3 prospective antiemetic studies conducted among Chinese breast cancer patients who received (neo)adjuvant AC, in order to identify optimal antiemetic prophylaxis. Methods: A total of 304 patients were included: Group 1, ondansetron/dexamethasone (D1); Group 2, aprepitant/ondansetron/dexamethasone (D1); Group 3, aprepitant/ondansetron/dexamethasone (D1–3); Group 4, aprepitant/ondansetron/dexamethasone (D1–3)/olanzapine; and Group 5, netupitant/palonosetron/dexamethasone (D1–3). Antiemetic efficacies of Groups 3, 4, and 5 during cycle 1 of AC were individually compared with Group 1. In addition, emesis outcomes of patients in Groups 3 and 5, and those of Groups 2 and 3, were compared. Results: When comparing efficacies of a historical doublet (5HT3RA/dexamethasone) with triplet antiemetic regimens (NK1RA/5HT3RA/dexamethasone) with/without olanzapine, complete response (CR) percentages and quality of life (QOL) in overall phase of cycle 1 AC were compared between Group 1 and the other groups: Group 1 vs. 3, 41.9% vs. 38.3% (P = 0.6849); Group 1 vs. 4, 41.9% vs. 65.0% (P = 0.0107); and Group 1 vs. 5, 41.9% vs. 60.0% (P = 0.0460). Groups 4 and 5 achieved a better QOL. When comparing netupitant-based (Group 3) with aprepitant-based (Group 5) triplet antiemetics, CR percentages were 38.3% vs. 60.0%, respectively (P = 0.0176); Group 5 achieved a better QOL. When comparing 1 day (Group 2) vs. 3 day (Group 3) dexamethasone, CR percentages were 46.8% and 38.3%, respectively (P = 0.3459); Group 3 had a worse QOL. Conclusions: Aprepitant-containing triplets were non-superior to doublet antiemetics. Netupitant-containing triplets and adding olanzapine to aprepitant-containing triplets were superior to doublets. Netupitant/palonosetron/dexamethasone was superior to aprepitant/ondansetron/dexamethasone. Protracted administration of dexamethasone provided limited additional benefit.

Introduction: In a prospective non-interventional study involving 2,173 patients, we showed that use of the oral fixed combination of netupitant 300 mg and palonosetron 0.5 mg (NEPA) for prevention of chemotherapy (Ctx)-induced nausea and vomiting has beneficial effects on the quality of life (QoL) of patients with various types of cancers receiving highly or moderately emetogenic Ctx. Here, we report on the effects on QoL, effectiveness, and tolerability of NEPA in patients with breast cancer exposed to anthracycline-cyclophosphamide (AC)-based Ctx. Methods: This is a post hoc subanalysis of a prospective non-interventional study in 1,197 patients with breast cancer receiving up to 3 cycles of doxorubicin or epirubicin plus cyclophosphamide and NEPA. NEPA administration was per the summary of product characteristics. Results: In cycle 1 of Ctx, a large proportion of patients (84%) reported "no impact on daily life" (NIDL) due to vomiting; 53% of patients reported NIDL due to nausea. The complete response rate was 86/88/81% in the acute/delayed/overall phase in cycle 1, and NEPA was well tolerated throughout the study. Conclusion: The real-world beneficial effects of NEPA prophylaxis on QoL were confirmed for patients with breast cancer receiving AC. NEPA was effective with a good safety profile in this patient population in clinical practice. [ABSTRACT FROM AUTHOR]

Considering the frequent use of netupitant in polytherapy, the elucidation of its oxidative metabolization pattern is of major importance. However, there is a lack of published research on the redox behavior of this novel neurokinin-1 receptor antagonist. Therefore, this study was performed to simulate the intensive hepatic biotransformation of netupitant using an electrochemically driven method. Most of the known enzyme-mediated reactions occurring in the liver (i.e., N -dealkylation, hydroxylation, and N -oxidation) were successfully mimicked by the electrolytic cell using a boron-doped diamond working electrode. The products were separated by reversed-phase high-performance liquid chromatography and identified by high-resolution mass spectrometry. Aside from its ability to pinpoint formerly unknown metabolites that could be responsible for the known side effects of netupitant or connected with any new perspective concerning future therapeutic indications, this electrochemical process also represents a facile alternative for the synthesis of oxidation products for further in vitro and in vivo studies. [Display omitted] • Study of the electrochemical behavior of netupitant, an NK 1 receptor antagonist. • Electrochemical simulation of the phase I oxidative metabolization of netupitant. • Identification of the generated oxidation species by LC/ESI(+)-MS. • Separation and identification of electrochemically generated isomers. [ABSTRACT FROM AUTHOR]

Background: To reduce the overall exposure to dexamethasone (DEX) in patients receiving cisplatin‐based chemotherapy, we evaluated the noninferiority of DEX on day 1, with or without low‐dose DEX on days 2 and 3, combined with an oral fixed‐dose combination of netupitant and palonosetron (NEPA), compared with the guideline‐consistent use of 4‐day DEX. Patients and Methods: In this open‐label, multicenter study, chemotherapy‐naïve patients undergoing high‐dose cisplatin (≥70 mg/m2), were given NEPA and DEX (12 mg) on day 1 and randomized (1:1:1 ratio) to receive either (a) no further DEX (DEX1), (b) oral DEX (4 mg daily) on days 2–3 (DEX3), or (c) DEX (4 mg twice daily) on days 2–4 (DEX4). The primary efficacy endpoint was complete response (CR: no emesis and no rescue medication) during the 5‐day overall phase. The noninferiority margin was set at −15% difference (DEX1 or DEX3 minus DEX4). Secondary efficacy endpoints included complete protection (CP: CR and none or mild nausea). Results: Two‐hundred twenty‐eight patients, 76 in each arm, were assessable. Noninferiority was met for both DEX‐sparing regimens and the reference arm, with overall phase CR rates of 76.3% in each of the DEX1 and DEX3 arms and 75.0% in the DEX4 arm (95% confidence interval, −12.3% to 15% for each comparison). During the overall phase, CP rates were similar between groups. Conclusion: A simplified regimen of NEPA plus single‐dose DEX offers comparable chemotherapy‐induced nausea and vomiting prevention throughout 5 days post‐chemotherapy with the advantage of sparing patients additional doses of DEX in the high–emetic‐risk setting of cisplatin‐based chemotherapy. Implications for Practice: Dexamethasone (DEX) has traditionally played an integral role in the management of chemotherapy‐induced emesis. Although generally considered safe, even short‐term DEX use is associated with various side effects, and some evidence suggests that concurrent steroids may reduce the efficacy of immunotherapies. This study demonstrates comparable antiemetic control during the 5 days post‐chemotherapy with a simplified regimen of netupitant/palonosetron plus single‐dose DEX versus the standard 4‐day DEX reference treatment in high‐dose cisplatin. This represents a clinically relevant achievement as it not only simplifies antiemetic prophylaxis but also offers an opportunity to appropriately use in patients where caution with corticosteroid use is advised. This study was designed to test whether two different dexamethasone‐sparing regimens, when administered with NEPA, might provide the opportunity to reduce the total corticosteroid dose while maintaining the same degree of chemotherapy‐induced nausea and vomiting control in patients undergoing cisplatin‐based chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract Aim To assess the efficacy of oral NEPA (netupitant‐palonosetron 300/0.50 mg) over multiple chemotherapy cycles. Methods Two randomized phase III studies evaluated a single dose of oral NEPA given on day 1 in chemotherapy‐naive patients receiving anthracycline‐cyclophosphamide (AC)–based (Study 1) or highly (HEC)/moderately (MEC) emetogenic chemotherapy (safety Study 2). Oral NEPA was compared with oral palonosetron 0.50 mg (Study 1) or oral aprepitant 125 mg day 1, 80 mg days 2‐3/palonosetron 0.50 mg (Study 2; no formal statistical comparisons). Oral dexamethasone was administered in all treatment groups. Complete response (CR; no emesis/no rescue medication), no emesis, and no significant nausea (NSN) rates during acute (0‐24 h) and delayed (>24‐120 h) phases of chemotherapy cycles 1‐4 in each study were evaluated. Results In Study 1, 1450 patients received 5969 chemotherapy cycles; in Study 2, 412 patients received 1961 chemotherapy cycles. In each study, ≥75% of patients completed 4 or more cycles. In Study 1, oral NEPA was superior to palonosetron in preventing chemotherapy‐induced nausea and vomiting (CINV) in the acute and delayed phases of cycle 1, with higher rates of CR (all P

Introduction: Antineoplastic drugs may induce several side effects, including chemotherapy-induced nausea and vomiting (CINV). Two neurotransmitters play a central role in mediating the emetic response: serotonin acting on the 5HT3 receptor and the substance P targeting the NK1 receptor. Indeed, a combination of a 5HT3 receptor antagonist (5HT3-RA) and a NK1 receptor antagonist (NK1-RA) together with dexamethasone has been shown to be very effective. In fact, this combination is actually widely used and recommended for CINV prophylaxis for highly emetogenic cisplatin-based adriamycin/cyclophosphamide (AC) and carboplatin-based regimens. NEPA (netupitant/palonosetron) is the only fixed combination antiemetic available and it is composed by the long-lasting second-generation 5HT3-RA palonosetron and the highly selective NK1-RA netupitant. Aim: The aims of this short review were to analyze the role of NEPA in CINV prophylaxis and management taking in account the risk factors related to the patient and to the antineoplastic treatment. Evidence Review: CINV development is not only correlated to the emetogenic potential of the antineoplastic drugs but is also very influenced by the patient characteristics and history, such as gender, age, alcohol intake, nausea during pregnancy and motion sickness. In pivotal and post-registration studies, NEPA has demonstrated to be effective and safe in both highly and moderately emetogenic chemotherapy. Conclusion: A proper assessment of both chemotherapy- and patient-related risk factors is paramount to properly evaluate an appropriate prophylaxis of CINV and NEPA by simplifying the therapy, guarantees fully adherence to antiemetic guidelines, and consequently improves the control of CINV, especially in high risk patients. [ABSTRACT FROM AUTHOR]

Background: NEPA, a combination antiemetic of a neurokinin‐1 (NK1) receptor antagonist (RA) (netupitant [oral]/fosnetupitant [intravenous; IV]) and 5‐HT3RA, palonosetron] offers 5‐day CINV prevention with a single dose. Fosnetupitant solution contains no allergenic excipients, surfactant, emulsifier, or solubility enhancer. A phase III study of patients receiving cisplatin found no infusion‐site or anaphylactic reactions related to IV NEPA. However, hypersensitivity reactions and anaphylaxis have been reported with other IV NK1RAs, particularly fosaprepitant in patients receiving anthracycline‐cyclophosphamide (AC)‐based chemotherapy. This study evaluated the safety and efficacy of IV NEPA in the AC setting. Materials and Methods: This phase IIIb, multinational, randomized, double‐blind study enrolled females with breast cancer naive to highly or moderately emetogenic chemotherapy. Patients were randomized to receive a single 30‐minute infusion of IV NEPA or single oral NEPA capsule on day 1 prior to AC, in repeated (up to 4) cycles. Oral dexamethasone was given to all patients on day 1 only. Results: A total of 402 patients were included. The adverse event (AE) profiles were similar for IV and oral NEPA and consistent with those expected. Most AEs were mild or moderate with a similarly low incidence of treatment‐related AEs in both groups. There were no treatment‐related injection‐site AEs and no reports of hypersensitivity or anaphylaxis. The efficacy of IV and oral NEPA were similar, with high complete response (no emesis/no rescue) rates observed in cycle 1 (overall [0–120 hours] 73.0% IV NEPA, 77.3% oral NEPA) and maintained over subsequent cycles. Conclusion: IV NEPA was highly effective and safe with no associated hypersensitivity and injection‐site reactions in patients receiving AC. Implications for Practice: As a combination of a neurokinin‐1 (NK1) receptor antagonist (RA) and 5‐HT3RA, NEPA offers 5‐day chemotherapy‐induced nausea and vomiting prevention with a single dose and an opportunity to improve adherence to antiemetic guidelines. In this randomized multinational phase IIIb study, intravenous (IV) NEPA (fosnetupitant/palonosetron) was safe and highly effective in patients receiving multiple cycles of anthracycline‐cyclophosphamide (AC)‐based chemotherapy. Unlike other IV NK1RAs, the IV NEPA combination solution does not require any surfactant, emulsifier, or solubility enhancer and contains no allergenic excipients. Hypersensitivity reactions and anaphylaxis have been reported with other IV NK1RAs, most commonly with fosaprepitant in the AC setting. Importantly, there were no injection‐site or hypersensitivity reactions associated with IV NEPA. Netupitant and palonosetron (NEPA) is a combination antiemetic that offers five‐day prevention of chemotherapy‐induced nausea and vomiting with a single dose. This article evaluates the safety and efficacy of intravenous NEPA in the setting of anthracycline/cyclophosphamide chemotherapy. [ABSTRACT FROM AUTHOR]

Background: The objective was to evaluate the cost-effectiveness of NEPA, an oral fixed combination netupitant (NETU, 300 mg) and palonosetron (PA, 0.5 mg) compared with aprepitant and palonosetron (APPA) or palonosetron (PA) alone, to prevent chemotherapy-induced nausea and vomiting (CINV) in patients undergoing treatment with highly or moderately emetogenic chemotherapy (HEC or MEC) in the UK. Scope: A systematic literature review and meta-analysis were undertaken to compare NEPA with currently recommended anti-emetics. Relative effectiveness was estimated over the acute (day 1) and overall treatment (days 1–5) phases, taking complete response (CR, no emesis and no rescue medication) and complete protection (CP, CR and no more than mild nausea [VAS scale

Background Chemotherapy-induced nausea and vomiting is a common and unpleasant treatment-related side effect reported by cancer patients receiving chemotherapy. Akynzeo® or NEPA (NEtupitant + PAlonosetron) is the first fixed combination of netupitant and palonosetron that targets both critical pathways involved in emesis while providing a convenient, single oral dose therapy. The current study aimed to assess the effectiveness and safety of NEPA in a real-world setting in India. Methodology This was an open-label, multicenter, prospective, single-arm study conducted at six different locations across India. The study included patients of either gender, aged ≥18 years, naive to chemotherapy, scheduled to receive highly or moderately emetogenic chemotherapy (HEC/MEC), and scheduled to receive oral NEPA, as determined by the investigator. Results A total of 360 people were screened and enrolled in the study. HEC was prescribed to 289 (81.64%) patients, while MEC was prescribed to 65 (18.36%) patients. Complete response was achieved in 94.92% of patients during the acute phase, 95.20% during the delayed phase, and 93.22% during the overall phase. During the overall phase, 92.73% and 95.38% of patients on the HEC and MEC regimens, respectively, achieved complete response. Adverse events were reported in 3.88% of patients. Conclusions Oral NEPA was found to be effective in the Indian real-world setting, eliciting a >90% complete response with HEC and MEC regimens across the acute, delayed, and overall phases., Competing Interests: Dr. Sagar Bhagat, Dr. Sumit Bhushan, Dr. Saiprasad Patil, and Dr. Hanmant Barkate are employees of Glenmark Pharmaceuticals Ltd. who contributed toward literature search, data analysis, and manuscript writing., (Copyright © 2024, Gupta et al.)

Chemotherapy-induced nausea and vomiting (CINV) can be prevented in most patients receiving appropriate antiemetic treatment. However, inadequate uptake of current antiemetic guideline recommendations by physicians, and poor treatment adherence by patients, lead to suboptimal CINV control. There is an unmet need to optimize guideline-consistent use of antiemetics to improve CINV management and prevention. Herein, we provide an overview of CINV, then discuss oral and intravenous NEPA, the first fixed combination antiemetic, composed of netupitant/fosnetupitant and palonosetron. We describe the main pharmacologic and pharmacokinetic characteristics of NEPA, and review the clinical evidence supporting its use in the prevention of CINV. [ABSTRACT FROM AUTHOR]

Vito Lorusso National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Bari, Italy Abstract: As recommended by most recent antiemetic guidelines, the optimal prophylaxis of chemotherapy-induced nausea and vomiting (CINV) requires the combination of 5-HT3 receptor antagonist (RA) with an NK1-RA. Moreover, the major predictors of acute and delayed CINV include: young age, female sex, platinum- or anthracycline-based chemotherapy, nondrinker status, emesis in the earlier cycles of chemotherapy, and previous history of motion/morning sickness. Despite improved knowledge of the pathophysiology of CINV and advances in the availability of active antiemetics, an inconsistent compliance with their use has been reported, thereby resulting in suboptimal control of CINV in several cases. In this scenario, a new antiemetic drug is now available, which seems to be able to guarantee better prophylaxis of CINV and improvement of adherence to guidelines. In fact, netupitant/palonosetron (NEPA) is a ready-to-use single oral capsule, combining an NK1-RA (netupitant) and a 5-HT3-RA (palonosetron), which is to be taken 1 hour before the administration of chemotherapy, ensuring the coverage from CINV for 5 days. We reviewed the role of NEPA in patients at high risk of CINV receiving highly emetogenic chemotherapy. In these patients, NEPA plus dexamethasone, as compared to standard treatments, achieved superior efficacy in all primary and secondary end points during the acute, delayed, and overall phases, including nausea assessment. Moreover, these results were also achieved in female patients receiving anthracycline plus cyclophosphamide-based chemotherapy. NEPA represents a real step forward in the prophylaxis of CINV. Keywords: NEPA, netupitant, NK1, CINV, vomiting, risk factors

Piotr K JanickiDepartment of Anesthesiology and Perioperative Medicine, Milton S Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, PA, USAPurpose: The purpose of this review is to summarize and discuss the recently published data (both original studies and reviews) on the oral medication NEPA, consisting of netupitant (a neurokinin-1 receptor antagonist [NK1RA], 300 mg dose) and palonosetron (5-hydroxytryptamine [serotonin or 5HT] type 3 receptor antagonist [5HT3RA], 0.5 mg dose), in the prevention of the acute and delayed nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy.Methods: This review was based on the very limited number of available published trials consisting of two Phase III studies and one Phase II dose-selecting trial.Results: These studies demonstrated some therapeutic benefits of NEPA over related chemotherapy-induced nausea and vomiting (CINV) prophylaxis management, as well as its beneficial safety profile. In particular, compared with single-dose 0.5 mg palonosetron, the complete response rates for all phases of CINV for the first cycle of highly emetogenic chemotherapy (with cisplatin), as well as anthracycline–cyclophosphamide-based moderately emetogenic chemotherapy, were significantly higher for single-dose NEPA. The high efficacy of NEPA in terms of prevention of CINV continued throughout repeated cycles of highly and moderately emetogenic therapies.Conclusion: It is currently recommended that patients who are administered highly emetogenic chemotherapy regimens should obtain a three-drug combination consisting of NK1RA, 5HT3RA, and dexamethasone. The recently available oral combination of NEPA plus dexa­methasone provides an additional pharmacological management option that could be considered in this scenario.Keywords: chemotherapy-induced nausea and vomiting, palonosetron, netupitant, NEPA, safety, pharmacology, outcomes

To examine pharmacologic and clinical characteristics of neurokinin 1 (NK1)-receptor antagonists (RAs) for preventing chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy, a literature search was performed for clinical studies in patients at risk of CINV with any approved NK1 RAs in the title or aprepitant (capsules or oral suspension), HTX019 (intravenous [IV] aprepitant), fosaprepitant (IV aprepitant prodrug), rolapitant (tablets or IV), and fixed-dose tablets combining netupitant or fosnetupitant (IV netupitant prodrug) with the 5-hydroxytryptamine type 3 (5HT3) RA palonosetron (oral or IV). All NK1 RAs are effective, but exhibit important differences in efficacy against acute and delayed CINV. The magnitude of benefit of NK1-RA-containing three-drug vs two-drug regimens is greater for delayed vs acute CINV. Oral rolapitant has the longest half-life of available NK1 RAs, but as a consequence should not be administered more frequently than every 2 weeks. In general, NK1 RAs are well tolerated; however, IV rolapitant was recently removed from US distribution, due to hypersensitivity and anaphylaxis, and IV fosaprepitant is associated with infusion-site reactions and hypersensitivity presumed related to its polysorbate 80 excipient. Also, available NK1 RAs have potential drug–drug interactions. Adding an NK1 RA to 5HT3 RA and dexamethasone significantly improves CINV control vs the two-drug regimen. Newer NK1 RAs offer more formulation options, higher acute-phase plasma levels, or improved tolerability, and increase clinicians' opportunities to maximize benefits of this important class of antiemetics. [ABSTRACT FROM AUTHOR]

Background: NEPA, an oral fixed combination of the NK1RA netupitant (300 mg) and clinically/pharmacologically distinct 5-HT3RA palonosetron (PALO, 0.50 mg), is the first fixed antiemetic combination to have been approved. A single oral NEPA capsule plus dexamethasone (DEX) given before anthracycline-cyclophosphamide (AC) and non-AC highly emetogenic chemotherapy (HEC) showed superior prevention of chemotherapy-induced nausea and vomiting (CINV) over PALO plus DEX for 5 days postchemotherapy. The safety of NEPA was well-established in the phase II/III clinical program in 1169 NEPA-treated patients. An intravenous (i.v.) formulation of the NEPA combination (fosnetupitant 235 mg plus PALO 0.25 mg) has been developed. Patients and methods: This randomized, multinational, double-blind, stratified (by sex and country) phase III study (NCT02517021) in chemotherapy-naïve patients with solid tumors assessed the safety of a single dose of i.v. NEPA infused over 30 min before initial and repeated cycles of HEC. Patients received either i.v. NEPA or oral NEPA, both with oral DEX on days 1-4. Safety was assessed primarily by treatment-emergent adverse events (AEs) and electrocardiograms. Results: A total of 404 patients completed 1312 cycles. The incidence and type of treatment-emergent AEs were similar for both treatment groups with the majority of AEs as mild/moderate in intensity. There was no increased incidence of AEs in subsequent cycles in either group. The incidence of treatment-related AEs was similar and relatively low in both groups (12.8% i.v. NEPA and 11.4% oral NEPA during the entire study), with constipation being the most common (6.4% i.v. NEPA, 6.0% oral NEPA). No serious treatment-related AEs occurred in either group. No infusion site or anaphylactic reactions related to i.v. NEPA occurred. No clinically relevant changes in QTc and no cardiac safety concerns were observed. Conclusions: Intravenous NEPA was well-tolerated with a similar safety profile to oral NEPA in patients with various solid tumors receiving HEC. [ABSTRACT FROM AUTHOR]

Background: Co-administration of multiple antiemetics that inhibit several molecular pathways involved in emesis is required to optimize chemotherapy-induced nausea and vomiting (CINV) control in patients receiving highly emetogenic chemotherapy (HEC). NEPA, a fixed combination of a highly selective NK1 receptor antagonist, netupitant (300 mg), and the pharmacologically distinct 5-HT3RA, palonosetron (PALO 0.50 mg), has shown superior CINV prevention compared with PALO in cisplatin and anthracycline/cyclophosphamide-based settings. This study is the first head-to-head comparison of NEPA versus an aprepitant (APR)/granisetron (GRAN) regimen. Patients and methods: This randomized, double-blind phase III study conducted in Asia was designed with the primary objective to demonstrate non-inferiority of a single oral dose of NEPA compared with a 3-day oral APR/GRAN regimen in chemotherapy-naïve patients receiving cisplatin-based HEC. All patients also received oral dexamethasone (DEX) on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis/no rescue medication) during the overall (0-120 h) phase. Non-inferiority was defined as a lower 95% CI greater than the non-inferiority margin set at -10%. Secondary efficacy endpoints included no emesis, no rescue medication, and no significant nausea (NSN). Results: Treatment groups were comparable for the 828 patients analyzed: predominantly male (71%); mean age 54.5 years; ECOG 0-1 (98%); lung cancer (58%). NEPA demonstrated non-inferiority to APR/GRAN for overall CR [NEPA 73.8% versus APR/GRAN 72.4%, 95% CI (-4.5%, 7.5%)]. No emesis [NEPA 75.0% versus APR/GRAN 74.0%, 95% CI (-4.8%, 6.9%)] and NSN rates [NEPA 75.7% versus APR/GRAN 70.4%, 95% CI (-0.6%, 11.4%)] were similar between groups, but significantly more NEPA patients did not take rescue medication [NEPA 96.6% versus APR/GRAN 93.5%, 95% CI (0.2%, 6.1%)]. NEPA was well tolerated with a similar safety profile to APR/GRAN. Conclusions: In this first study comparing NK1RA regimens and DEX, NEPA administered only on day 1 was non-inferior to a 3-day oral APR/GRAN regimen in preventing CINV associated with HEC. [ABSTRACT FROM AUTHOR]

Introduction. Tachykinins potently contract the isolated urinary bladder from a number of animal species and play an important role in the regulation of the micturition reflex. On the guinea-pig isolated urinary bladder we examined the effects of a new potent and selective NK1 receptor antagonist (netupitant) on the contractions induced by a selective NK1 receptor agonist, SP-methylester (SP-OMe). Moreover, the effects of netupitant and another selective NK1 antagonist (L-733,060) were studied in anesthetized guinea-pigs using two experimental models, the isovolumetric bladder contractions and a model of bladder overactivity induced by intravesical administration of acetic acid (AA). Methods and Results. Detrusor muscle strips were mounted in 5 mL organ baths and isometric contractions to cumulative concentrations of SP-OME were recorded before and after incubation with increasing concentrations of netupitant. In anesthetized female guinea-pigs, reflex bladder activity was examined under isovolumetric conditions with the bladder distended with saline or during cystometry using intravesical infusion of acetic acid (AA). After a 30 min stabilization period, netupitant (0.1-3 mg/kg, i.v.) or L-733,060 (3-10 mg/kg, i.v.) were administered. In the detrusor muscle, netupitant produced a concentration-dependent inhibition (mean pKB = 9.24) of the responses to SP-OMe. Under isovolumetric conditions, netupitant or L-733,060 reduced bladder contraction frequency in a dose-dependent manner, but neither drug changed bladder contraction amplitude. In the AA model, netupitant dose-dependently increased intercontraction interval (ICI) but had no effect on the amplitude of micturition (AM). L-733,060 dose-dependently increased ICI also but this effect was paralleled by a significant reduction of AM. Conclusion. Netupitant decreases the frequency of reflex bladder contractions without altering their amplitude, suggesting that this drug targets the afferent limb of the micturition reflex circuit and therefore may be useful clinically in treating bladder overactivity symptoms.

Chemotherapy-induced nausea and vomiting (CINV), both acute and delayed, has a dramatic effect on the well-being and quality of life of patients with cancer. Improved understanding of the mechanisms involved in CINV has led to the development of agents targeting the 5-HT3 receptor as well as the NK-1 receptor. Antiemetic prophylaxis given to patients receiving highly emetogenic chemotherapy combines agents blocking the 5-HT3 and NK-1 receptors along with corticosteroids given regularly and repeatedly. Rolapitant is a long-acting NK-1 receptor antagonist with proven efficacy in controlling CINV as part of the prophylaxis regimen. This review will detail the clinical efficacy and safety of rolapitant in the treatment of patients with cancer receiving highly or moderately emetogenic chemotherapy. [ABSTRACT FROM AUTHOR]