Netupitant

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Netupitant
File:Netupitant.svg
Clinical data
License data
Drug classNK1 receptor antagonists, antiemetics
ATC code
  • None
Pharmacokinetic data
Bioavailability>60% (estimated)
Protein binding>99%
Metabolismmainly CYP3A4; also CYP2D6 and CYP2C9
Elimination half-life88 hours
Excretion71% (faeces)
Identifiers
  • 2-[3,5-Bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]propanamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E number{{#property:P628}}
CompTox Dashboard (EPA)
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Chemical and physical data
FormulaC30H32F6N4O
Molar mass578.603 g·mol−1
3D model (JSmol)
  • Cc1ccccc1c2cc(ncc2N(C)C(=O)C(C)(C)c3cc(cc(c3)C(F)(F)F)C(F)(F)F)N4CCN(CC4)C
  • 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,10-13H2,1-5H3
  • Key:WAXQNWCZJDTGBU-UHFFFAOYSA-N

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]

Adverse effects

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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]

Interactions

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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] The clinical relevance of the anti-cancer drug interactions has been questioned.[5]

Pharmacology

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Mechanism of action

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Netupitant is a selective NK1 receptor antagonist.[6]

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.[7]

Pharmacokinetics

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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][8]

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.[9]

File:Netupitant metabolites.svg
Netupitant metabolites[8]

References

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