Trade names Akynzeo Legal status US: ℞-only Protein binding >99% | Routes of
administration Oral Bioavailability >60% (estimated) Molar mass 578.59 g/mol | |
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Metabolism | ||
Netupitant is an antiemitic 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.
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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.
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.
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 NK1 receptor antagonist.
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%.
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.