aprepitant and netupitant

Antiemetic guideline recommendations are inconsistent as to whether a neurokinin-1 receptor antagonist (NK1 RA) should be administered with a 5-hydroxytryptamine-3 (5HT3) RA + dexamethasone (DEX) in patients receiving carboplatin. Patients receiving cisplatin routinely receive an NK1 RA-containing regimen with a resulting 14-22 % benefit in no emesis rates over a 5-HT3 RA/DEX control. Recent studies suggest a similar benefit in patients receiving carboplatin. NEPA is the first fixed antiemetic combination agent and comprises the highly selective NK1 RA, netupitant, and pharmacologically distinct 5-HT3 RA, palonosetron (PALO). This paper presents the efficacy of NEPA in the subset of patients receiving carboplatin in a phase 3 trial (NCT01376297), in the context of aprepitant (APR) data in the carboplatin setting.. One hundred ninety-six patients (47 % of all study patients: n = 145 NEPA + DEX; n = 51 APR + PALO + DEX) received carboplatin in a multinational, double-blind, randomized phase 3 study. Complete response (CR: no emesis/rescue) and no significant nausea (NSN: score ≤25 on 100 mm visual analog scale) rates were calculated.. Cycle 1-4 overall (0-120 h) CR rates were similar for NEPA (80, 91, 92, and 93 %) and APR (82, 88, 88, and 90 %). Overall NSN rates were also similar (NEPA 84-96 %; APR 82-90 %).. Response rates for NEPA and APR regimens were similar and consistent with prior studies evaluating the contribution of adding NK1 RAs in patients receiving carboplatin. Considering such evidence, guideline groups/practitioners should consider giving a NK1 RA antiemetic triplet in patients receiving carboplatin.

Topics: Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Carboplatin; Double-Blind Method; Female; Humans; Isoquinolines; Male; Middle Aged; Morpholines; Palonosetron; Pyridines; Quinuclidines; Receptors, Neurokinin-1

The hypothesis that sustained G protein-coupled receptor (GPCR) signaling from endosomes mediates pain is based on studies with endocytosis inhibitors and lipid-conjugated or nanoparticle-encapsulated antagonists targeted to endosomes. GPCR antagonists that reverse sustained endosomal signaling and nociception are needed. However, the criteria for rational design of such compounds are ill-defined. Moreover, the role of natural GPCR variants, which exhibit aberrant signaling and endosomal trafficking, in maintaining pain is unknown. Herein, substance P (SP) was found to evoke clathrin-mediated assembly of endosomal signaling complexes comprising neurokinin 1 receptor (NK

Topics: Animals; Aprepitant; Endosomes; Humans; Mice; Pain; Receptors, G-Protein-Coupled; Receptors, Neurokinin-1; Substance P

The aim of this study was to assess the cost-effectiveness of NEPA, a fixed-dose combination of oral netupitant (300 mg) and palonosetron (0.5 mg), compared to available treatments in Spain after aprepitant generic introduction in the market, and to discuss results in previously performed analyses in different wordwide settings.. A Markov model including three health states, complete protection, complete response at best and incomplete response, was used to evaluate the cost-effectiveness of NEPA versus common treatment options in Spain during 5 days after chemotherapy. Incremental costs including treatment costs and treatment failure management cost as well as incremental effects including quality adjusted life days (QALDs) and emesis-free days were compared between NEPA and the comparator arms. The primary outcomes were cost per avoided emetic event and cost per QALDs gained.. NEPA was dominant (more effective and less costly) against aprepitant combined with palonosetron, and fosaprepitant combined with granisetron, while, compared to generic aprepitant plus ondansetron, NEPA showed an incremental cost per avoided emetic event of €33 and cost per QALD gained of €125.. By most evaluations, NEPA is a dominant or cost-effective treatment alternative to current antiemetic standards of care in Spain during the first 5 days of chemotherapy treatment in cancer patients, despite the introduction of generics. These results are in line with previously reported analyses throughout different international settings.

Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Cost-Benefit Analysis; Emetics; Humans; Internationality; Nausea; Palonosetron; Quinuclidines; Vomiting

To assess, from a United States (US) perspective, the cost-effectiveness of chemotherapy-induced nausea and vomiting (CINV) prophylaxis using a single dose of netupitant and palonosetron in a fixed combination (NEPA) versus aprepitant plus granisetron (APR + GRAN), each in combination with dexamethasone, in chemotherapy-naïve patients receiving highly emetogenic chemotherapy (HEC).. We analyzed patient-level outcomes over a 5-day post-HEC period from a randomized, double-blind, phase 3 clinical trial of NEPA (n = 412) versus APR + GRAN (n = 416). Costs and CINV-related utilities were assigned to each subject using published sources. Parameter uncertainty was addressed via multivariate probabilistic sensitivity analyses (PSA).. Compared to APR + GRAN, NEPA resulted in a gain of 0.09 quality-adjusted life-days (QALDs) (4.04 vs 3.95; 95% CI -0.06 to 0.25) and a significant total per-patient cost reduction of $309 ($943 vs $1252; 95% CI $4-$626), due principally to $258 in lower medical costs of CINV-related events ($409 vs $668; 95% CI -$46 to $572) and $45 in lower study drug costs ($531 vs $577). In the PSA, NEPA resulted in lower costs and higher QALD in 86.5% of cases and cost ≤ $25,000 per quality-adjusted life-year gained in 97.8% of cases.. This first-ever economic analysis using patient-level data from a phase 3 trial comparing neurokinin-1 receptor antagonist (NK1 RA) antiemetic regimens suggests that NEPA is highly cost-effective (and in fact cost-saving) versus an aprepitant-based regimen in post-HEC CINV prevention. Actual savings may be higher, as we focused only on the first chemotherapy cycle and omitted the impact of CINV-related chemotherapy discontinuation.

Topics: Antiemetics; Aprepitant; Cost-Benefit Analysis; Drug Therapy, Combination; Female; Granisetron; Humans; Male; Middle Aged; Nausea; Palonosetron; Pyridines; Vomiting

Neurokinins (or tachykinins) are peptides that modulate a wide variety of human physiology through the neurokinin G protein-coupled receptor family, implicated in a diverse array of pathological processes. Here we report high-resolution crystal structures of the human NK

Topics: Aprepitant; Binding Sites; Crystallography, X-Ray; Drug Design; HEK293 Cells; Humans; Molecular Dynamics Simulation; Neurokinin-1 Receptor Antagonists; Piperidines; Protein Structure, Secondary; Pyridines; Receptors, Neurokinin-1; Recombinant Proteins; Structure-Activity Relationship

Topics: Antiemetics; Aprepitant; Humans; Nausea; Palonosetron; Pyridines; Vomiting

Chemotherapy-induced nausea and vomiting is a significant clinical issue which affects patient's quality of life and treatment decisions. Significant improvements in the control of chemotherapy-induced nausea and vomiting have occurred in the past 15 years with the introduction of new antiemetic agents 5-HT3, receptor antagonists, neurokinin-1 (NK-1) receptor antagonists, and olanzapine. Aprepitant was the first NK-1 receptor antagonist introduced (2003) for the prevention of chemotherapy-induced nausea and vomiting in combination with a 5-HT3 receptor antagonist and dexamethasone. A second NK-1 receptor antagonist netupitant was approved for use in October 2014. Phase III clinical trials of an additional NK-1 receptor antagonist rolapitant have been completed, and the data have been submitted for regulatory approval. A description of rolapitant and its role in chemotherapy-induced nausea and vomiting will be presented, along with a comparison of the other neurolinin-1 receptor antagonists aprepitant and netupitant.

Topics: Animals; Antiemetics; Antineoplastic Agents; Aprepitant; Humans; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Pyridines; Quality of Life; Spiro Compounds; Vomiting