Netupitant

Netupitant is an antiemetic drug. In the United States, the combination drug netupitant/palonosetron (trade name Akynzeo) is approved by the Food and Drug Administration for prevention of acute and delayed chemotherapy-induced nausea and vomiting, including highly emetogenic chemotherapy such as with cisplatin.[1] In Europe, it is approved by the European Medicines Agency for the same indication.[2]

Netupitant
Clinical data
Trade namesAkynzeo
License data
Routes of
administration		Oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability>60% (estimated)
Protein binding>99%
Metabolismmainly CYP3A4; also CYP2D6 and CYP2C9
Elimination half-life88 hours
Excretion71% (faeces)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC30H32F6N4O
Molar mass578.59 g/mol g·mol−1
3D model (JSmol)

Adverse effects

Side effects of the combination netupitant/palonosetron are similar to palonosetron alone, so that no common side effects can be attributed to netupitant.[2]

headache, weakness, indigestion, fatigue, constipation, and skin redness

Interactions

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.[2]

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.[2]

Pharmacology

Mechanism of action

Netupitant is a selective NK1 receptor antagonist.[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.[4]

Pharmacokinetics

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%.[2]

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.[2][5]

Netupitant and its metabolites are mainly excreted via the faeces.[2] 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.[6]

Netupitant metabolites[5]

References
  1. "FDA approves Akynzeo for nausea and vomiting associated with cancer chemotherapy". Food and Drug Administration. October 10, 2014.
  2. "Akynzeo: Summary of Product Characteristics" (PDF). European Medicines Agency. Retrieved 12 July 2016.
  3. 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.
  4. https://pubchem.ncbi.nlm.nih.gov/compound/Netupitant#section=Top
  5. 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.
  6. Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
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