Identification

Name
Netupitant
Accession Number
DB09048
Type
Small Molecule
Groups
Approved, Investigational
Description

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.

Structure
Thumb
Synonyms
  • 2-[3,5-Bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]propanamide
External IDs
RO 67-3189/000
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
AkynzeoNetupitant (300 mg) + Palonosetron (0.5 mg)CapsuleOralPurdue Pharma2017-11-20Not applicableCanada
AkynzeoNetupitant (300 mg/1) + Palonosetron (0.5 mg/1)CapsuleOralHelsinn Therapeutics (U.S.), Inc2014-10-13Not applicableUs
AkynzeoNetupitant (300 mg/1) + Palonosetron (0.5 mg/1)CapsuleOralEisai Limited2014-10-132018-05-31Us
Categories
UNII
7732P08TIR
CAS number
290297-26-6
Weight
Average: 578.603
Monoisotopic: 578.248030644
Chemical Formula
C30H32F6N4O
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

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.

Associated Conditions
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
ASubstance-P receptor
antagonist
Human
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.

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).

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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Netupitant.
AbirateroneThe serum concentration of Netupitant can be increased when it is combined with Abiraterone.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Netupitant.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Netupitant.
Acetyl sulfisoxazoleThe metabolism of Netupitant can be decreased when combined with Acetyl sulfisoxazole.
AdinazolamThe serum concentration of Adinazolam can be increased when it is combined with Netupitant.
AgmatineThe serum concentration of Agmatine can be increased when it is combined with Netupitant.
AlbendazoleThe serum concentration of Albendazole can be increased when it is combined with Netupitant.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Netupitant.
AlfentanilThe serum concentration of Alfentanil can be increased when it is combined with Netupitant.
Food Interactions
Not Available

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. [PubMed:25687374]
External Links
KEGG Drug
D10572
PubChem Compound
6451149
PubChem Substance
310264992
ChemSpider
4953629
BindingDB
50178574
ChEBI
85155
ChEMBL
CHEMBL206253
Wikipedia
Netupitant
FDA label
Download (273 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Not Yet RecruitingSupportive CareChemotherapy Induced Nausea Vomiting1
2RecruitingPreventionProphylaxis of acute chemotherapy induced nausea and vomiting1
2RecruitingSupportive CareHematopoietic Cell Transplantation Recipient / Hematopoietic Stem Cell Transplantation (HSCT) / Nausea / Neoplasms, Malignant / Vomiting1
2, 3RecruitingSupportive CareIn Situ Neoplasm / Nausea and Vomiting, Chronic / Neoplasms, Malignant1
3CompletedPreventionProphylaxis of acute chemotherapy induced nausea and vomiting3
3RecruitingPreventionProphylaxis of acute chemotherapy induced nausea and vomiting1
3RecruitingSupportive CareCarcinoma, Breast1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9186357No2010-11-182030-11-18Us
US8623826No2010-11-182030-11-18Us
US8951969No2010-11-182030-11-18Us
US6297375No2000-02-222020-02-22Us
US9271975No2011-09-092031-09-09Us
US9943515No2010-11-182030-11-18Us
US9951016No2015-09-252035-09-25Us

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/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
N-arylpiperazine / 4-phenylpyridine / Pyridinylpiperazine / Phenylacetamide / Trifluoromethylbenzene / Phenylpropane / Dialkylarylamine / Toluene / N-alkylpiperazine / N-methylpiperazine
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)

Targets

Kind
Protein
Organism
Human
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. [PubMed:25687374]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Yes
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. [PubMed:23748441]
Kind
Protein
Organism
Human
Pharmacological action
Yes
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. [PubMed:23748441]
Kind
Protein
Organism
Human
Pharmacological action
Yes
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. [PubMed:23748441]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. [PubMed:23729226]

Drug created on May 04, 2015 10:50 / Updated on September 07, 2018 03:24