Identification
- Summary
Netupitant is an antiemetic agent used in combination with palonosetron to prevent acute and delayed vomiting and nausea caused by chemotherapy.
- Brand Names
- Akynzeo
- Generic Name
- Netupitant
- DrugBank Accession Number
- DB09048
- Background
Netupitant is an antiemitic drug approved by the FDA in October 2014 for use in combination with palonosetron for the prevention of acute and delayed vomiting and nausea associated with cancer chemotherapy including highly emetogenic chemotherapy. Netupitant is a neurokinin 1 receptor antagonist. The combination drug is marketed by Eisai Inc. and Helsinn Therapeutics (U.S.) Inc. under the brand Akynzeo.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Netupitant (DB09048)
- Weight
- Average: 578.603
Monoisotopic: 578.248030644 - Chemical Formula
- C30H32F6N4O
- Synonyms
- 2-[3,5-Bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]propanamide
- Netupitant
- External IDs
- RO 67-3189/000
Pharmacology
- Indication
Netupitant is an antiemitic drug approved by the FDA in October 2014 for use in combination with palonosetron for the prevention of acute and delayed vomiting and nausea associated with cancer chemotherapy including highly emetogenic chemotherapy.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination for prophylaxis of Acute chemotherapy-induced nausea and vomiting Combination Product in combination with: Palonosetron (DB00377) •••••••••••• Used in combination for prophylaxis of Delayed nausea and vomiting caused by chemotherapy Combination Product in combination with: Palonosetron (DB00377) •••••••••••• - Contraindications & Blackbox Warnings
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Not Available
- Mechanism of action
Delayed emesis (vomiting) has been largely associated with the activation of tachykinin family neurokinin 1 (NK1) receptors (broadly distributed in the central and peripheral nervous systems) by substance P. As shown in in vitro and in vivo studies, netupitant inhibits substance P mediated responses.
Target Actions Organism ANeurokinin 1 receptor antagonistHumans - Absorption
Upon oral administration of a single dose of netupitant, netupitant started to be measurable in plasma between 15 minutes and 3 hours after dosing. Plasma concentrations reached Cmax in approximately 5 hours. There was a greater than dose-proportional increase in the systemic exposure with the dose increase from 10 mg to 300 mg and a dose-proportional increase in systemic exposure with a dose increase from 300 mg to 450 mg.
- Volume of distribution
In cancer patients, Vz/F: 1982 ± 906 L (mean ± SD).
- Protein binding
> 99.5% at drug concentrations ranging from 10-1300 ng/mL.
- Metabolism
Once absorbed, netupitant is extensively metabolized to form three major metabolites: desmethyl derivative, M1; N-oxide derivative, M2; and OH-methyl derivative, M3. Metabolism is mediated primarily by CYP3A4 and to a lesser extent by CYP2C9 and CYP2D6. Metabolites M1, M2 and M3 were shown to bind to the substance P/neurokinin 1 (NK1) receptor.
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- Route of elimination
Primarily fecal.
- Half-life
96 hours with CV% of 61.
- Clearance
Estimated systemic clearance of 20.3 ± 9.2 L/h (mean ± SD).
- Adverse Effects
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Daily oral administration of netupitant in rats at doses up to 30 mg/kg (1.9 times the human AUC in male rats and 3.7 times the human AUC in female rats at the recommended human dose) had no effects on fertility or reproductive performance.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The metabolism of 1,2-Benzodiazepine can be decreased when combined with Netupitant. Abametapir The serum concentration of Netupitant can be increased when it is combined with Abametapir. Abatacept The metabolism of Netupitant can be increased when combined with Abatacept. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Netupitant. Abiraterone The metabolism of Netupitant can be decreased when combined with Abiraterone. - Food Interactions
- Avoid grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of netupitant, which may increase its serum concentration.
- Avoid St. John's Wort. This herb induces the CYP3A metabolism of netupitant and may reduce its serum concentration.
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Akynzeo Netupitant (235 mg) + Palonosetron hydrochloride (0.25 mg) Injection, powder, for solution Intravenous Helsinn Birex Pharmaceuticals Ltd 2020-12-22 Not applicable EU 
AKYNZEO Netupitant (300 MG) + Palonosetron (0.5 MG) Capsule Oral Helsinn Birex Pharmaceuticals Ltd 2015-07-30 Not applicable Italy 
Akynzeo Netupitant (300 mg/1) + Palonosetron (0.5 mg/1) Capsule Oral Helsinn Therapeutics (U.S.), Inc. 2014-10-13 Not applicable US 
Akynzeo Netupitant (300 mg) + Palonosetron hydrochloride (0.50 mg) Capsule Oral Helsinn Birex Pharmaceuticals Ltd 2020-12-22 Not applicable EU AKYNZEO Netupitant (300 MG) + Palonosetron (0.5 MG) Capsule Oral Helsinn Birex Pharmaceuticals Ltd 2019-03-01 Not applicable Italy
Categories
- Drug Categories
- Acetamides
- Amides
- BCRP/ABCG2 Inhibitors
- Benzene Derivatives
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (moderate)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates (strength unknown)
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Netupitant and prodrug
- Neurokinin 1 Antagonists
- P-glycoprotein inhibitors
- Substance P/Neurokinin-1 Receptor Antagonist
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as pyridinylpiperazines. These are compounds containing a pyridinylpiperazine skeleton, which consists of a pyridine linked (not fused) to a piperazine by a bond by a single bond that is not part of a ring.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Diazinanes
- Sub Class
- Piperazines
- Direct Parent
- Pyridinylpiperazines
- Alternative Parents
- N-arylpiperazines / Phenylpyridines / Trifluoromethylbenzenes / Phenylacetamides / Phenylpropanes / Dialkylarylamines / Toluenes / N-methylpiperazines / Aminopyridines and derivatives / Imidolactams show 11 more
- Substituents
- 4-phenylpyridine / Alkyl fluoride / Alkyl halide / Amine / Amino acid or derivatives / Aminopyridine / Aromatic heteromonocyclic compound / Azacycle / Benzenoid / Carbonyl group show 27 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- organofluorine compound, N-arylpiperazine, monocarboxylic acid amide, ring assembly, N-alkylpiperazine, toluenes, aminopyridine (CHEBI:85155)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 7732P08TIR
- CAS number
- 290297-26-6
- InChI Key
- WAXQNWCZJDTGBU-UHFFFAOYSA-N
- 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
- IUPAC Name
- 2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl]propanamide
- SMILES
- CN(C(=O)C(C)(C)C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)C1=CN=C(C=C1C1=CC=CC=C1C)N1CCN(C)CC1
References
- General References
- Darmani NA, Zhong W, Chebolu S, Mercadante F: Differential and additive suppressive effects of 5-HT3 (palonosetron)- and NK1 (netupitant)-receptor antagonists on cisplatin-induced vomiting and ERK1/2, PKA and PKC activation. Pharmacol Biochem Behav. 2015 Apr;131:104-11. doi: 10.1016/j.pbb.2015.02.010. Epub 2015 Feb 14. [Article]
- External Links
- KEGG Drug
- D10572
- PubChem Compound
- 6451149
- PubChem Substance
- 310264992
- ChemSpider
- 4953629
- BindingDB
- 50178574
- 1552337
- ChEBI
- 85155
- ChEMBL
- CHEMBL206253
- ZINC
- ZINC000011681563
- PDBe Ligand
- GAW
- Wikipedia
- Netupitant
- PDB Entries
- 6hlp
- FDA label
- Download (273 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Recruiting Supportive Care Chemotherapy-Induced Nausea and Vomiting 1 4 Unknown Status Supportive Care Oncology 1 3 Completed Prevention Chemotherapy-Induced Nausea and Vomiting 4 3 Recruiting Supportive Care Breast Carcinoma 1 3 Unknown Status Supportive Care Chemotherapy-Induced Nausea and Vomiting 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral Injection, powder, for solution Intravenous Injection, solution, concentrate Intravenous Capsule, gelatin coated Oral - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9186357 No 2015-11-17 2030-11-18 US US8623826 No 2014-01-07 2030-11-18 US US8951969 No 2015-02-10 2030-11-18 US US6297375 No 2001-10-02 2020-02-22 US US9271975 No 2016-03-01 2031-09-09 US US9943515 No 2018-04-17 2030-11-18 US US9951016 No 2018-04-24 2035-09-25 US US10233154 No 2019-03-19 2035-09-25 US US10676440 No 2020-06-09 2035-09-25 US US10828297 No 2020-11-10 2030-12-17 US US10961195 No 2021-03-30 2035-09-25 US US11559523 No 2010-11-18 2030-11-18 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00285 mg/mL ALOGPS logP 5.48 ALOGPS logP 7.26 Chemaxon logS -5.3 ALOGPS pKa (Strongest Basic) 7.6 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 39.68 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 148.59 m3·mol-1 Chemaxon Polarizability 55.88 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule Yes Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 223.6411 predictedDeepCCS 1.0 (2019) [M+H]+ 225.5365 predictedDeepCCS 1.0 (2019) [M+Na]+ 231.31468 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Tachykinin receptor activity
- Specific Function
- This is a receptor for the tachykinin neuropeptide substance P. It is probably associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of aff...
- Gene Name
- TACR1
- Uniprot ID
- P25103
- Uniprot Name
- Substance-P receptor
- Molecular Weight
- 46250.5 Da
References
- Darmani NA, Zhong W, Chebolu S, Mercadante F: Differential and additive suppressive effects of 5-HT3 (palonosetron)- and NK1 (netupitant)-receptor antagonists on cisplatin-induced vomiting and ERK1/2, PKA and PKC activation. Pharmacol Biochem Behav. 2015 Apr;131:104-11. doi: 10.1016/j.pbb.2015.02.010. Epub 2015 Feb 14. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Monooxygenase activity
- Specific Function
- Exhibits low testosterone 6-beta-hydroxylase activity.
- Gene Name
- CYP3A43
- Uniprot ID
- Q9HB55
- Uniprot Name
- Cytochrome P450 3A43
- Molecular Weight
- 57669.21 Da
References
- Calcagnile S, Lanzarotti C, Rossi G, Henriksson A, Kammerer KP, Timmer W: Effect of netupitant, a highly selective NK(1) receptor antagonist, on the pharmacokinetics of palonosetron and impact of the fixed dose combination of netupitant and palonosetron when coadministered with ketoconazole, rifampicin, and oral contraceptives. Support Care Cancer. 2013 Oct;21(10):2879-87. doi: 10.1007/s00520-013-1857-9. Epub 2013 Jun 11. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Calcagnile S, Lanzarotti C, Rossi G, Henriksson A, Kammerer KP, Timmer W: Effect of netupitant, a highly selective NK(1) receptor antagonist, on the pharmacokinetics of palonosetron and impact of the fixed dose combination of netupitant and palonosetron when coadministered with ketoconazole, rifampicin, and oral contraceptives. Support Care Cancer. 2013 Oct;21(10):2879-87. doi: 10.1007/s00520-013-1857-9. Epub 2013 Jun 11. [Article]
- Netupitant FDA Label [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- Calcagnile S, Lanzarotti C, Rossi G, Henriksson A, Kammerer KP, Timmer W: Effect of netupitant, a highly selective NK(1) receptor antagonist, on the pharmacokinetics of palonosetron and impact of the fixed dose combination of netupitant and palonosetron when coadministered with ketoconazole, rifampicin, and oral contraceptives. Support Care Cancer. 2013 Oct;21(10):2879-87. doi: 10.1007/s00520-013-1857-9. Epub 2013 Jun 11. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Lanzarotti C, Rossi G: Effect of netupitant, a highly selective NK(1) receptor antagonist, on the pharmacokinetics of midazolam, erythromycin, and dexamethasone. Support Care Cancer. 2013 Oct;21(10):2783-91. doi: 10.1007/s00520-013-1855-y. Epub 2013 Jun 1. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
Drug created at May 04, 2015 16:50 / Updated at October 07, 2021 12:08