Netupitant

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
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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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination for prophylaxis ofAcute chemotherapy-induced nausea and vomitingCombination Product in combination with: Palonosetron (DB00377)••••••••••••
Used in combination for prophylaxis ofDelayed nausea and vomiting caused by chemotherapyCombination Product in combination with: Palonosetron (DB00377)••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

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.

TargetActionsOrganism
ANeurokinin 1 receptor
antagonist
Humans
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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Toxicity

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.
DrugInteraction
1,2-BenzodiazepineThe metabolism of 1,2-Benzodiazepine can be decreased when combined with Netupitant.
AbametapirThe serum concentration of Netupitant can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Netupitant can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Netupitant.
AbirateroneThe 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

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
AkynzeoNetupitant (235 mg) + Palonosetron hydrochloride (0.25 mg)Injection, powder, for solutionIntravenousHelsinn Birex Pharmaceuticals Ltd2020-12-22Not applicableEU flag
AKYNZEONetupitant (300 MG) + Palonosetron (0.5 MG)CapsuleOralHelsinn Birex Pharmaceuticals Ltd2015-07-30Not applicableItaly flag
AkynzeoNetupitant (300 mg/1) + Palonosetron (0.5 mg/1)CapsuleOralHelsinn Therapeutics (U.S.), Inc.2014-10-13Not applicableUS flag
AkynzeoNetupitant (300 mg) + Palonosetron hydrochloride (0.50 mg)CapsuleOralHelsinn Birex Pharmaceuticals Ltd2020-12-22Not applicableEU flag
AKYNZEONetupitant (300 MG) + Palonosetron (0.5 MG)CapsuleOralHelsinn Birex Pharmaceuticals Ltd2019-03-01Not applicableItaly flag

Categories

Drug Categories
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
  1. 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]
KEGG Drug
D10572
PubChem Compound
6451149
PubChem Substance
310264992
ChemSpider
4953629
BindingDB
50178574
RxNav
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);">
PhaseStatusPurposeConditionsCount
4RecruitingSupportive CareChemotherapy-Induced Nausea and Vomiting1
4Unknown StatusSupportive CareOncology1
3CompletedPreventionChemotherapy-Induced Nausea and Vomiting4
3RecruitingSupportive CareBreast Carcinoma1
3Unknown StatusSupportive CareChemotherapy-Induced Nausea and Vomiting1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral
Injection, powder, for solutionIntravenous
Injection, solution, concentrateIntravenous
Capsule, gelatin coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9186357No2015-11-172030-11-18US flag
US8623826No2014-01-072030-11-18US flag
US8951969No2015-02-102030-11-18US flag
US6297375No2001-10-022020-02-22US flag
US9271975No2016-03-012031-09-09US flag
US9943515No2018-04-172030-11-18US flag
US9951016No2018-04-242035-09-25US flag
US10233154No2019-03-192035-09-25US flag
US10676440No2020-06-092035-09-25US flag
US10828297No2020-11-102030-12-17US flag
US10961195No2021-03-302035-09-25US flag
US11559523No2010-11-182030-11-18US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00285 mg/mLALOGPS
logP5.48ALOGPS
logP7.26Chemaxon
logS-5.3ALOGPS
pKa (Strongest Basic)7.6Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area39.68 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity148.59 m3·mol-1Chemaxon
Polarizability55.88 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-0001090000-91fa25acc9de361d5c30
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-0000090000-c0a0cbd4372fd122d15f
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-056r-0031090000-5021b6d03bc4c044d002
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-1000190000-c769413516663d47d7a3
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00fr-0163090000-20fae6df13d8002dd235
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4j-0130190000-81ffb6fad9963530d854
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-223.6411
predicted
DeepCCS 1.0 (2019)
[M+H]+225.5365
predicted
DeepCCS 1.0 (2019)
[M+Na]+231.31468
predicted
DeepCCS 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
  1. 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
  1. 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
  1. 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]
  2. 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
  1. 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
Inhibitor
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
  1. 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