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NEPA is the only fixed combination antiemetic, comprised of an NK1RA (netupitant) and a 5‐HT3RA (palonosetron). In the first head‐to‐head trial to compare NK1RA‐containing regimens, a single oral dose of NEPA was non‐inferior to a 3‐day aprepitant/granisetron (APR/GRAN) regimen for the primary endpoint of overall (0‐120 hours) complete response (no emesis/no rescue). This pre‐specified analysis evaluates the efficacy of NEPA versus APR/GRAN in the subset of Chinese patients in the study. In addition, efficacy in patients at greatest emetic risk receiving high‐dose cisplatin (≥70 mg/m2) was explored. Chemotherapy‐naïve patients with solid tumors in this randomized, double‐blind study received either a single dose of NEPA prior to cisplatin‐based chemotherapy or a 3‐day regimen of APR/GRAN, both with dexamethasone on Days 1‐4. Efficacy was evaluated through complete response, no emesis, and no significant nausea rates during the acute (0‐24 hours), delayed (25‐120 hours) and overall phases as well as individual days post‐chemotherapy, as the daily course of CINV protection is often unstudied. The Chinese subset included 667 patients; of these, 363 (54%) received high‐dose cisplatin. Baseline characteristics were comparable. While response rates were similar for NEPA and APR/GRAN during the acute, delayed and overall phases, significantly fewer NEPA patients experienced breakthrough CINV on individual Days 3‐5 in both the Chinese patients and also in those receiving high‐dose cisplatin. As a fixed oral NK1RA/5HT3RA combination given once/cycle, NEPA is a convenient highly effective prophylactic antiemetic that may offer better protection from CINV than a 3‐day APR/GRAN regimen on Days 3‐5 following highly emetogenic chemotherapy., NEPA is a novel fixed combination antiemetic comprised of the NK1RA, netupitant, and the 5‐HT3RA, palonosetron. The simultaneous targeting of two critical antiemetic pathways, in unison with single‐dose administration, offers a simplified and convenient antiemetic with 5‐day CINV prevention. The authors report significantly better protection from CINV during Days 3‐5 post‐chemotherapy for NEPA vs a 3‐day regimen of aprepitant/granisetron in Chinese patients, and in those receiving high‐dose cisplatin, in the first head‐to‐head study comparing NK1RA‐containing regimens.

Purpose Palonosetron hydrochloride is a specific 5-HT3 receptor antagonist, used to prevent chemotherapy-induced nausea and vomiting (CINV), and is a known chemical entity currently registered in the oral and IV forms in several countries worldwide. Methods Single-center, single-dose, 3-treatment, open-label, randomized, 3-period, phase-I cross-over study, conducted in 18 individuals (16 males and 2 females). The primary objective was to assess the pharmacokinetic profile of Palonosetron 0.25, 0.5 and 0.75mg, after a single, oral administration in Chinese male and female healthy volunteers. Results After administration of a single oral dose of 0.25mg, 0.5mg, or 0.75mg palonosetron in Chinese male and female healthy subjects, plasma palonosetron concentrations reached maximum values (Cmax) of 673 ± 151 pg/mL, 1330 ± 258 pg/mL, and 1990 ± 490 pg/mL, respectively, at 3-5 h (tmax). The plasma elimination half-life for 0.25, 0.5 and 0.75 mg of palonosetron was 41.8±9.72 hours, 44.6±8.59 hours and 42.3±8.51 hours, respectively. Single oral doses of 0.25mg, 0.5mg, or 0.75mg palonosetron were safe and well tolerated among all the 18 subjects involved. Conclusions The PK of palonosetron was found to be linear in the dose range of 0.25 to 0.75 mg. Oral palonosetron in doses up to 0.75 mg was well tolerated in healthy Chinese subjects. The PK and safety data obtained from this study were similar to previous phase I studies with IV palonosetron.

Oral NEPA, the only fixed-combination antiemetic, is composed of the neurokinin-1 receptor antagonist netupitant (300 mg) and the 5-hydroxytryptamine-3 receptor antagonist palonosetron (0.50 mg). This study was conducted to evaluate the pharmacokinetic profile of netupitant and its main metabolites M1 and M3, and palonosetron in Chinese subjects. Oral NEPA tolerability and safety were also analyzed. This was a single-center, single-dose phase 1 study in healthy, adult Chinese volunteers. Eligible subjects received oral NEPA, and blood samples were collected on day 1 predose and at various time points up until day 10 postdose. Pharmacokinetic parameters were analyzed using noncompartmental methods. For safety assessments, adverse events (AEs) were monitored during the study. In total 18 Chinese healthy volunteers received oral NEPA. Netupitant mean maximum plasma concentration (Cmax) [± standard deviation] of 698 ± 217 ng/mL was reached at 3–6 h, with a mean total exposure (AUC0–inf) of 22,000 ± 4410 h·ng/mL. For palonosetron, a mean Cmax of 1.8 ± 0.252 ng/mL was reached at 2–6 h postadministration, with a mean AUC0–inf of 81.0 ± 14.0 h·ng/mL. The most common treatment-related AEs in > 2 subjects were constipation (n = 9) and tiredness (n = 3). No severe AEs were observed, and no subject withdrew due to AEs. Following single-dose administration of oral NEPA in Chinese subjects, the pharmacokinetic profiles of the NEPA components were mostly similar to those reported previously in Caucasians. NEPA was well tolerated with a safety profile in line with that observed in pivotal trials in Caucasians.

Antiemetic treatment compliance is important to prevent chemotherapy-induced nausea and vomiting, a feared chemotherapy side effect. NEPA, a new oral fixed combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron, a second-generation 5-HT3 RA, targets dual antiemetic pathways with a single dose. This study investigated the effect of food intake and age on NEPA pharmacokinetics (PK) and safety. In this open-label, single-center, randomized, phase 1 study, 24 adults (18-45 years) received NEPA in a fed or fasted state during the first treatment period and in the alternative state in the next treatment period. Twelve elderly subjects (≥65 years) received NEPA in a fasted state. Blood samples were taken for netupitant and palonosetron PK analysis. In the fed condition, netupitant plasma exposure increased, whereas palonosetron PK parameters were not affected. Furthermore, elderly subjects showed increased netupitant and palonosetron exposure compared with adults. All adverse events were mild/moderate, with constipation and headache the most common. Although food intake and age altered NEPA PK, dose adjustments were not needed, as netupitant and palonosetron exposure increases did not lead to safety concerns in healthy subjects.

Netupitant is a new, selective NK1 receptor antagonist under development for the prevention of chemotherapy-induced nausea and vomiting. Two studies were conducted to evaluate the brain receptor occupancy (RO) and disposition (ADME) of netupitant in humans. Positron emission tomography (PET) imaging with the NK1 receptor-binding-selective tracer [(11) C]-GR205171 was used to evaluate the brain penetration of different doses of netupitant (100, 300, and 450 mg) and to determine the NK1 -RO duration. A NK1 -RO of 90% or higher was achieved with all doses in the majority of the tested brain regions at Cmax, with a long duration of RO. The netupitant minimal plasma concentration predicted to achieve a NK1 -RO of 90%, C90% , in the striatum was 225 ng/mL; after administration of netupitant 300 mg, concentrations exceeded the C90% . In the ADME study, a single nominal dose of [(14) C]-netupitant 300 mg was used to assess its disposition. Absorption was rapid and netupitant was extensively metabolized via Phase I and II hepatic metabolism. Elimination of90% was predicted at day 29 and was principally via hepatic/biliary route (85%) with a minor contribution of the renal route (5%). In conclusion, these studies demonstrate that netupitant is a potent agent targeting NK1 receptors with long lasting RO. In addition, netupitant is extensively metabolized and is mainly eliminated through the hepatic/biliary route and to a lesser extent via the kidneys.

Neurokinin-1 receptor antagonists (NK1 RAs) are commonly coadministered with a 5-HT3 RA such as palonosetron to prevent nausea and vomiting induced by chemotherapy. Netupitant, a new highly selective NK1 RA, is both a substrate for and a moderate inhibitor of CYP3A4. Three studies were designed to evaluate the potential drug–drug interaction of netupitant with palonosetron and of the fixed dose combination of netupitant and palonosetron, NEPA, with an inhibitor (ketoconazole), an inducer (rifampicin) and a substrate (oral contraceptives) of CYP3A4. Study 1 was a three-way crossover in 18 healthy subjects receiving netupitant alone, palonosetron alone, and the combination of both antiemetics. Studies 2 and 3 were two-way crossover trials where healthy subjects received NEPA (the fixed dose combination of netupitant and palonosetron). In study 2, 36 subjects received NEPA alone (day 1) and in combination with ketoconazole or rifampicin. In study 3, 24 healthy women received ethinylestradiol/levonorgestrel alone or in combination with NEPA (day 1). There were no significant pharmacokinetic interactions between netupitant and palonosetron. Ketoconazole increased netupitant area under curve (AUC) by 140 % and C max by 25 %. Rifampicin decreased netupitant AUC by 83 % and C max by 62 %. NEPA did not significantly affect exposure to ethinylestradiol, while systemic exposure to levonorgestrel increased by 40 %, but this was not considered clinically relevant. There were no clinically relevant interactions between netupitant and palonosetron, or between NEPA and oral contraceptives. The coadministration of NEPA with inhibitors or inducers of CYP3A4 may require dose adjustments. Treatments were well tolerated.

Netupitant is a new highly selective neurokinin-1 receptor antagonist being studied for the prevention of nausea and vomiting in patients undergoing chemotherapy. In vitro studies suggest that netupitant inhibits the cytochrome P-450 isoenzyme 3A4 (CYP3A4). Because netupitant may be used with a variety of drugs, which may be substrates of CYP3A4, two studies were designed to establish the potential risk for drug–drug interaction with three different CYP3A4 substrates: midazolam, erythromycin, and dexamethasone. Both trials were three-period crossover studies performed in healthy subjects. In the first study, 20 subjects received netupitant and either midazolam or erythromycin. In the second study, 25 subjects received netupitant and dexamethasone. Serial blood samples were collected over the course of the two studies and pharmacokinetic parameters were determined for all analytes. Netupitant, by inhibiting the CYP3A4, increased the C max and AUCinf of midazolam by 40 and 144 %, respectively, and the C max and AUCinf of erythromycin by 30 %. Netupitant was shown to increase the exposure to dexamethasone in a dose-dependent manner with the mean increase in AUC and C max by 72 and 11 %, respectively, on day 1 and by 138 and 75 %, respectively, on day 4 when co-administered with 300 mg of netupitant. The results of these studies suggest that netupitant is a moderate inhibitor of CYP3A4 and therefore, co-administration with drugs that are substrates of CYP3A4 may require dose adjustments. Treatments were well tolerated in both studies.

Neurokinin-1 (NK1) receptor antagonists (RAs) are commonly coadministered with serotonin (5-HT3) RAs (e.g. palonosetron (PALO)) to prevent chemotherapy-induced nausea/vomiting. Netupitant/palonosetron (NEPA), an oral fixed combination of netupitant (NETU)—a new NK1 RA—and PALO, is currently under development. In vitro data suggest that NETU inhibits CYP3A4 and is a substrate for and weak inhibitor of P-glycoprotein (P-gp). This review evaluates potential drug–drug interactions between NETU or NEPA and CYP3A4 substrates/inducers/inhibitors or P-gp substrates in healthy subjects. Pharmacokinetic (PK) parameters were evaluated for each drug when NETU was coadministered with PALO (single doses) and when single doses of NETU or NEPA were coadministered with CYP3A4 substrates (erythromycin (ERY), midazolam (MID), dexamethasone (DEX), or oral contraceptives), inhibitors (ketoconazole (KETO)), or inducers (rifampicin (RIF)), or a P-gp substrate (digoxin (DIG)). Results showed no relevant PK interactions between NETU and PALO. Coadministration of NETU increased MID and ERY exposure and significantly increased DEX exposure in a dose-dependent manner; NETU exposure was unaffected. NEPA coadministration had no clinically significant effect on oral contraception, although levonorgestrel exposure increased. NETU exposure increased after coadministration of NEPA with KETO and decreased after coadministration with RIF; PALO exposure was unaffected. NETU coadministration did not influence DIG exposure. In conclusion, there were no clinically relevant interactions between NETU and PALO, or NEPA and oral contraceptives (based on levonorgestrel and ethinylestradiol exposure). Coadministration of NETU or NEPA with CYP3A4 inducers/inhibitors/substrates should be done with caution. Dose reduction is recommended for DEX. Dose adjustments are not needed for NETU coadministration with P-gp substrates.

120 Background: Antiemetic trials typically evaluate CINV control during acute (Day 1), delayed (Days 2-5), and overall (Days 1-5) phases post-chemotherapy; the daily course of events is often unstudied in the delayed phase. In a head-to-head study evaluating NK1RA-containing regimens, a single dose of NEPA, an oral fixed combination of the NK1RA netupitant and 5-HT3RA palonosetron, was non-inferior to a 3-day regimen of APR and GRAN for overall complete response (no emesis/no rescue use) rates (74% NEPA vs 72% APR/GRAN) in 828 patients receiving cisplatin-based highly emetogenic chemotherapy (HEC). This secondary analysis explores daily rates of breakthrough CINV in this study. Methods: This was a double-blind study in chemotherapy-naïve patients with solid tumors. Daily rates of breakthrough CINV, defined as the % of patients with emesis and/or rescue use were calculated with differences between treatment groups evaluated by the Cochran-Mantel-Haenszel method stratified by sex. Results: While daily rates of patients with breakthrough CINV remained stable between 13%-15.1% for APR/GRAN, they declined from 15.5% to 8% over the 5 days for NEPA, with the difference between groups reaching statistical significance on Day 5 (Table). Percent of total patient days with CINV events were 11.7% [NEPA] and 14.0% [APR/GRAN]. The % of patients with ≥ 3 days of breakthrough CINV were 8.5% and 12.3%, respectively. Conclusions: In this study evaluating guideline-recommended antiemetic regimens for HEC, CINV was prevented in most patients during the overall phase yet breakthrough CINV on individual days differed between treatment groups. APR/GRAN showed a relatively constant rate over time, while NEPA rates decreased and patients had fewer total days with breakthrough. This suggests the need for close monitoring of CINV events during the delayed phase. [Table: see text]

10090 Background: Co-administration of multiple antiemetics that inhibit several molecular pathways involved in emesis is required to optimize CINV control in patients receiving highly emetogenic chemotherapy (HEC). NEPA, a novel fixed combination of a highly selective NK1 receptor antagonist (RA), netupitant (300 mg), and palonosetron (PALO 0.50 mg), a pharmacologically distinct 5-HT3RA, has shown superior CINV prevention compared to PALO in cisplatin and AC-based settings. This study is the first head-to-head comparison of NEPA versus an aprepitant (APR)/granisetron (GRAN) regimen, with the primary objective being to demonstrate non-inferiority in preventing CINV. Methods: This randomized, double-blind, parallel group Phase III study conducted in an Asian population was designed to compare efficacy and safety of a single oral dose of NEPA 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 and no significant nausea (NSN: < 25mm on 100mm VAS). 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; no emesis and NSN rates favored NEPA. Most frequent study drug-related adverse events (AEs) for NEPA included constipation (8.0%) and hiccups (2.7%). The type/incidence/severity of AEs were similar for NEPA and APR/GRAN. Conclusions: In this first study comparing NK1RA regimens and 4 days of DEX, NEPA administered only on day 1 was non-inferior to a 3-day oral APR/GRAN regimen in preventing CINV associated with HEC. [Table: see text]

Antiemetic treatment compliance is important to prevent chemotherapy-induced nausea and vomiting, a feared chemotherapy side effect. NEPA, a new oral fixed combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron, a second-generation 5-HT3 RA, targets dual antiemetic pathways with a single dose. This study investigated the effect of food intake and age on NEPA pharmacokinetics (PK) and safety. In this open-label, single-center, randomized, phase 1 study, 24 adults (18-45 years) received NEPA in a fed or fasted state during the first treatment period and in the alternative state in the next treatment period. Twelve elderly subjects (≥65 years) received NEPA in a fasted state. Blood samples were taken for netupitant and palonosetron PK analysis. In the fed condition, netupitant plasma exposure increased, whereas palonosetron PK parameters were not affected. Furthermore, elderly subjects showed increased netupitant and palonosetron exposure compared with adults. All adverse events were mild/moderate, with constipation and headache the most common. Although food intake and age altered NEPA PK, dose adjustments were not needed, as netupitant and palonosetron exposure increases did not lead to safety concerns in healthy subjects.

Netupitant is a new highly selective neurokinin-1 receptor antagonist being studied for the prevention of nausea and vomiting in patients undergoing chemotherapy. In vitro studies suggest that netupitant inhibits the cytochrome P-450 isoenzyme 3A4 (CYP3A4). Because netupitant may be used with a variety of drugs, which may be substrates of CYP3A4, two studies were designed to establish the potential risk for drug-drug interaction with three different CYP3A4 substrates: midazolam, erythromycin, and dexamethasone.Both trials were three-period crossover studies performed in healthy subjects. In the first study, 20 subjects received netupitant and either midazolam or erythromycin. In the second study, 25 subjects received netupitant and dexamethasone. Serial blood samples were collected over the course of the two studies and pharmacokinetic parameters were determined for all analytes.Netupitant, by inhibiting the CYP3A4, increased the C max and AUCinf of midazolam by 40 and 144 %, respectively, and the C max and AUCinf of erythromycin by 30 %. Netupitant was shown to increase the exposure to dexamethasone in a dose-dependent manner with the mean increase in AUC and C max by 72 and 11 %, respectively, on day 1 and by 138 and 75 %, respectively, on day 4 when co-administered with 300 mg of netupitant.The results of these studies suggest that netupitant is a moderate inhibitor of CYP3A4 and therefore, co-administration with drugs that are substrates of CYP3A4 may require dose adjustments. Treatments were well tolerated in both studies.

Neurokinin-1 receptor antagonists (NK1 RAs) are commonly coadministered with a 5-HT3 RA such as palonosetron to prevent nausea and vomiting induced by chemotherapy. Netupitant, a new highly selective NK1 RA, is both a substrate for and a moderate inhibitor of CYP3A4. Three studies were designed to evaluate the potential drug-drug interaction of netupitant with palonosetron and of the fixed dose combination of netupitant and palonosetron, NEPA, with an inhibitor (ketoconazole), an inducer (rifampicin) and a substrate (oral contraceptives) of CYP3A4.Study 1 was a three-way crossover in 18 healthy subjects receiving netupitant alone, palonosetron alone, and the combination of both antiemetics. Studies 2 and 3 were two-way crossover trials where healthy subjects received NEPA (the fixed dose combination of netupitant and palonosetron). In study 2, 36 subjects received NEPA alone (day 1) and in combination with ketoconazole or rifampicin. In study 3, 24 healthy women received ethinylestradiol/levonorgestrel alone or in combination with NEPA (day 1).There were no significant pharmacokinetic interactions between netupitant and palonosetron. Ketoconazole increased netupitant area under curve (AUC) by 140 % and C max by 25 %. Rifampicin decreased netupitant AUC by 83 % and C max by 62 %. NEPA did not significantly affect exposure to ethinylestradiol, while systemic exposure to levonorgestrel increased by 40 %, but this was not considered clinically relevant.There were no clinically relevant interactions between netupitant and palonosetron, or between NEPA and oral contraceptives. The coadministration of NEPA with inhibitors or inducers of CYP3A4 may require dose adjustments. Treatments were well tolerated.