Netupitant

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]

Netupitant

Clinical data
License data	EU EMA: by INN
Drug class	NK1 receptor antagonists, antiemetics
ATC code	None
Pharmacokinetic data
Bioavailability	>60% (estimated)
Protein binding	>99%
Metabolism	mainly CYP3A4; also CYP2D6 and CYP2C9
Elimination half-life	88 hours
Excretion	71% (faeces)
Identifiers
IUPAC name 2-[3,5-Bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]propanamide
CAS Number	290297-26-6
PubChem CID	6451149
DrugBank	DB09048
ChemSpider	4953629
UNII	7732P08TIR
KEGG	D05152
ChEBI	CHEBI:85155
ChEMBL	ChEMBL206253
CompTox Dashboard (EPA)	DTXSID50183271
Chemical and physical data
Formula	C30H32F6N4O
Molar mass	578.603 g·mol−1
3D model (JSmol)	Interactive image
SMILES Cc1ccccc1c2cc(ncc2N(C)C(=O)C(C)(C)c3cc(cc(c3)C(F)(F)F)C(F)(F)F)N4CCN(CC4)C
InChI 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

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.^[3][1]

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.^[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

Mechanism of action

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

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]

Netupitant metabolites^[8]