Side effects of the combination netupitant/palonosetron are similar to palonosetron alone, so that no common side effects can be attributed to netupitant.[3][1]
InteractionsEdit
Netupitant blood plasma levels are expected to increase when combined with inhibitors of the liver enzyme CYP3A4 and lowered when combined with inductors of this enzyme.[3]
Being a CYP3A4 inhibitor itself, netupitant could also increase plasma levels of pharmaceuticals that are metabolized by CYP3A4. This effect has been observed with dexamethasone, the anti-cancer drugs docetaxel and etoposide, and to a minor (not clinically significant) extent with levonorgestrel, erythromycin and midazolam.[3]
Netupitant is a selective neurokinin 1 (NK1) receptor antagonist with potential antiemetic activity. Netupitant competitively binds to and blocks the activity of the human substance P/NK1 receptors in the central nervous system (CNS), thereby inhibiting NK1-receptor binding of the endogenous tachykinin neuropeptide substance P (SP), which may result in the prevention of chemotherapy-induced nausea and vomiting (CINV). SP is found in neurons of vagal afferent fibers innervating the brain-stem nucleus tractus solitarii and the area postrema, which contains the chemoreceptor trigger zone (CTZ), and may be elevated in response to chemotherapy. The NK-receptor is a G-protein receptor coupled to the inositol phosphate signal-transduction pathway and is found in both the nucleus tractus solitarii and the area postrema.[6]
PharmacokineticsEdit
Bioavailability is estimated to be over 60% for orally taken netupitant. Highest blood plasma concentrations are reached five hours after application. Availability is moderately (10–20%) increased when taken after a fatty meal. Netupitant and its main metabolites (called M1 and M3) are bound to plasma proteins to more than 99%, and M2 protein binding is 97%.[3]
The substance is mainly metabolized by CYP3A4, and to a lesser extent by CYP2D6 and CYP2C9. The main metabolites are desmethyl-netupitant (M1), netupitant N-oxide (M2), and hydroxy-netupitant (M3); all three are pharmacologically active.[3][7]
Netupitant and its metabolites are mainly excreted via the faeces.[3]Biological half-life is 88 hours, significantly longer than that of the first NK1 receptor antagonist, aprepitant, which has a half-life of 9 to 13 hours.[8]
^ ab"Akynzeo- netupitant and palonosetron capsule Akynzeo- fosnetupitant and palonosetron injection". DailyMed. 30 April 2018. from the original on 18 October 2020. Retrieved 19 March 2020.
^ (Press release). Food and Drug Administration. October 10, 2014. Archived from the original on February 1, 2017. Retrieved December 16, 2019.
^ abcdefg"Akynzeo: Summary of Product Characteristics" (PDF). European Medicines Agency. (PDF) from the original on 26 June 2016. Retrieved 12 July 2016.
^"Akynzeo EPAR". European Medicines Agency (EMA). 19 March 2020. from the original on 19 March 2020. Retrieved 19 March 2020.
^Rizzi A, Campi B, Camarda V, Molinari S, Cantoreggi S, Regoli D, Pietra C, Calo G (2012). "In vitro and in vivo pharmacological characterization of the novel NK(1) receptor selective antagonist netupitant". Peptides. 37 (1): 86–97. doi:10.1016/j.peptides.2012.06.010. PMID 22732666. S2CID 7982557.
^"Netupitant". from the original on 2019-01-01. Retrieved 2018-12-31.
^ abSpinelli, T; Calcagnile, S; Giuliano, C; Rossi, G; Lanzarotti, C; Mair, S; Stevens, L; Nisbet, I (2013). "Netupitant PET imaging and ADME studies in humans". The Journal of Clinical Pharmacology. 54 (1): 97–108. doi:10.1002/jcph.198. PMC4282341. PMID 24122871.
^Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
External linksEdit
"Netupitant". Drug Information Portal. U.S. National Library of Medicine.
"Netupitant mixture with palonosetron". Drug Information Portal. U.S. National Library of Medicine.
netupitant, antiemetic, medication, united, states, combinations, netupitant, palonosetron, prodrug, fosnetupitant, palonosetron, both, brand, name, akynzeo, approved, food, drug, administration, prevention, acute, delayed, chemotherapy, induced, nausea, vomit. Netupitant is an antiemetic medication In the United States the combinations of netupitant palonosetron and the prodrug fosnetupitant palonosetron both brand name Akynzeo are approved by the Food and Drug Administration for the prevention of acute and delayed chemotherapy induced nausea and vomiting including highly emetogenic chemotherapy such as with cisplatin 1 2 In the European Union the combinations are approved by the European Medicines Agency EMA for the same indication 3 4 NetupitantClinical dataLicense dataEU EMA by INNATC codeNonePharmacokinetic dataBioavailability gt 60 estimated Protein binding gt 99 Metabolismmainly CYP3A4 also CYP2D6 and CYP2C9Elimination half life88 hoursExcretion71 faeces IdentifiersIUPAC name 2 3 5 Bis trifluoromethyl phenyl N 2 dimethyl N 4 2 methylphenyl 6 4 methyl 1 piperazinyl 3 pyridinyl propanamideCAS Number290297 26 6PubChem CID6451149DrugBankDB09048ChemSpider4953629UNII7732P08TIRKEGGD05152ChEBICHEBI 85155ChEMBLChEMBL206253CompTox Dashboard EPA DTXSID50183271Chemical and physical dataFormulaC 30H 32F 6N 4OMolar mass578 603 g mol 13D model JSmol Interactive imageSMILES Cc1ccccc1c2cc ncc2N C C O C C C c3cc cc c3 C F F F C F F F N4CCN CC4 CInChI InChI 1S C30H32F6N4O c1 19 8 6 7 9 23 19 24 17 26 40 12 10 38 4 11 13 40 37 18 25 24 39 5 27 41 28 2 3 20 14 21 29 31 32 33 16 22 15 20 30 34 35 36 h6 9 14 18H 10 13H2 1 5H3Key WAXQNWCZJDTGBU UHFFFAOYSA N Contents 1 Adverse effects 2 Interactions 3 Pharmacology 3 1 Mechanism of action 3 2 Pharmacokinetics 4 References 5 External linksAdverse effects EditSide effects of the combination netupitant palonosetron are similar to palonosetron alone so that no common side effects can be attributed to netupitant 3 1 Interactions EditNetupitant blood plasma levels are expected to increase when combined with inhibitors of the liver enzyme CYP3A4 and lowered when combined with inductors of this enzyme 3 Being a CYP3A4 inhibitor itself netupitant could also increase plasma levels of pharmaceuticals that are metabolized by CYP3A4 This effect has been observed with dexamethasone the anti cancer drugs docetaxel and etoposide and to a minor not clinically significant extent with levonorgestrel erythromycin and midazolam 3 Pharmacology EditMechanism of action Edit Netupitant is a selective NK1 receptor antagonist 5 Netupitant is a selective neurokinin 1 NK1 receptor antagonist with potential antiemetic activity Netupitant competitively binds to and blocks the activity of the human substance P NK1 receptors in the central nervous system CNS thereby inhibiting NK1 receptor binding of the endogenous tachykinin neuropeptide substance P SP which may result in the prevention of chemotherapy induced nausea and vomiting CINV SP is found in neurons of vagal afferent fibers innervating the brain stem nucleus tractus solitarii and the area postrema which contains the chemoreceptor trigger zone CTZ and may be elevated in response to chemotherapy The NK receptor is a G protein receptor coupled to the inositol phosphate signal transduction pathway and is found in both the nucleus tractus solitarii and the area postrema 6 Pharmacokinetics Edit Bioavailability is estimated to be over 60 for orally taken netupitant Highest blood plasma concentrations are reached five hours after application Availability is moderately 10 20 increased when taken after a fatty meal Netupitant and its main metabolites called M1 and M3 are bound to plasma proteins to more than 99 and M2 protein binding is 97 3 The substance is mainly metabolized by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C9 The main metabolites are desmethyl netupitant M1 netupitant N oxide M2 and hydroxy netupitant M3 all three are pharmacologically active 3 7 Netupitant and its metabolites are mainly excreted via the faeces 3 Biological half life is 88 hours significantly longer than that of the first NK1 receptor antagonist aprepitant which has a half life of 9 to 13 hours 8 Netupitant metabolites 7 References Edit a b Akynzeo netupitant and palonosetron capsule Akynzeo fosnetupitant and palonosetron injection DailyMed 30 April 2018 Archived from the original on 18 October 2020 Retrieved 19 March 2020 FDA approves Akynzeo for nausea and vomiting associated with cancer chemotherapy Press release Food and Drug Administration October 10 2014 Archived from the original on February 1 2017 Retrieved December 16 2019 a b c d e f g Akynzeo Summary of Product Characteristics PDF European Medicines Agency Archived PDF from the original on 26 June 2016 Retrieved 12 July 2016 Akynzeo EPAR European Medicines Agency EMA 19 March 2020 Archived from the original on 19 March 2020 Retrieved 19 March 2020 Rizzi A Campi B Camarda V Molinari S Cantoreggi S Regoli D Pietra C Calo G 2012 In vitro and in vivo pharmacological characterization of the novel NK 1 receptor selective antagonist netupitant Peptides 37 1 86 97 doi 10 1016 j peptides 2012 06 010 PMID 22732666 S2CID 7982557 Netupitant Archived from the original on 2019 01 01 Retrieved 2018 12 31 a b Spinelli T Calcagnile S Giuliano C Rossi G Lanzarotti C Mair S Stevens L Nisbet I 2013 Netupitant PET imaging and ADME studies in humans The Journal of Clinical Pharmacology 54 1 97 108 doi 10 1002 jcph 198 PMC 4282341 PMID 24122871 Haberfeld H ed 2015 Austria Codex in German Vienna Osterreichischer Apothekerverlag External links Edit Netupitant Drug Information Portal U S National Library of Medicine Netupitant mixture with palonosetron Drug Information Portal U S National Library of Medicine Portal Medicine Retrieved from https en wikipedia org w index php title Netupitant amp oldid 1166040083, wikipedia, wiki, book, books, library,
