|Metabolism||mainly CYP3A4; also CYP2D6 and CYP2C9|
|Elimination half-life||88 hours|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||578.59 g/mol g·mol−1|
|3D model (JSmol)|
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. In Europe, it is approved by the European Medicines Agency for the same indication.
Side effects of the combination netupitant/palonosetron are similar to palonosetron alone, so that no common side effects can be attributed to netupitant.
headache, weakness, indigestion, fatigue, constipation, and skin redness
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.
Mechanism of action
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.
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%.
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.
Netupitant and its metabolites are mainly excreted via the faeces. 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.
- "FDA approves Akynzeo for nausea and vomiting associated with cancer chemotherapy". Food and Drug Administration. October 10, 2014.
- "Akynzeo: Summary of Product Characteristics" (PDF). European Medicines Agency. Retrieved 12 July 2016.
- 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.
- 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: Österreichischer Apothekerverlag.