Identification

Name
Neratinib
Accession Number
DB11828
Description

Neratinib was approved in July 2017 for use as an extended adjuvant therapy in Human Epidermal Growth Factor Receptor 2 (HER2) positive breast cancer. Approval was granted to Puma Biotechnology Inc. for the tradename Nerlynx. Neratinib is currently under investigation for use in many other forms of cancer.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 557.05
Monoisotopic: 556.1989665
Chemical Formula
C30H29ClN6O3
Synonyms
  • Neratinib
External IDs
  • HKI-272

Pharmacology

Indication

For use as an extended adjuvant treatment in adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy [FDA Label].

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Neratinib is a tyrosine kinase inhibitor which exhibits antitumor action against Epidermal Growth Factor Receptor (EGFR), HER2, and Human Epidermal Growth Factor Receptor 4 (HER4) postive carcinomas [FDA Label].

Mechanism of action

Neratinib binds to and irreversibly inhibits EGFR, HER2, and HER4 [FDA Label]. This prevents auotphoshorylation of tyrosine residues on the receptor and reduces oncogenic signalling through the mitogen-activated protein kinase and Akt pathways.

TargetActionsOrganism
AEpidermal growth factor receptor
inhibitor
Humans
Absorption

Neratinib and its major active metabolites M3. M6, and M7 have a Tmax of 2-8 h [FDA Label]. Administration with a high fat meal increases Cmax by 1.7-fold and total exposure by 2.2-fold. Administration with a standard meal increases Cmax by 1.2-fold and total exposure by 1.1-fold. Administration with gastric acid reducing agents such as proton pump inhibitors reduces Cmax by 71% and total exposure by 65%.

Volume of distribution

The apparent volume of distribution at steady state is 6433 L [FDA Label].

Protein binding

Neratinib is over 99% bound to human plasma proteins [FDA Label]. It binds both human serum albumin and α1 acid glycoprotein.

Metabolism

Neratinib is mainly undergoes metabolism via CYP3A4 [FDA Label]. It is also metabolized by flavin-containing monooxygenase to a lesser extent. The systemic exposures of neratinib's active metabolites M3, M6, M7, and M11 are 15%, 33%, 22%, and 4%.

Route of elimination

97.1% of the total dose is excreted in the feces and 1.13% in the urine [FDA Label].

Half-life

The mean half life of elimination ranges from 7-17 h following a single dose [FDA Label]. The mean plasma half life during multiple doses is 14.6 h for neratinib, 21.6 h for M3, 13.8 h for M6, and 10.4 h for M7.

Clearance

The total clearance during multiple doses is 216 L/h for after the first dose and 281 L/h during steady state [FDA Label].

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

Use of neratinib may produce diarrhea and hepatotoxicity as clinically significant adverse effects [FDA Label]. Serious adverse reactions in the neratinib arm of the clinical trials included diarrhea (1.6%), vomiting (0.9%), dehydration (0.6%), cellulitis (0.4%), renal failure (0.4%), erysipelas (0.4%), alanine aminotransferase increase (0.3%), aspartate aminotransferase increase (0.3%), nausea (0.3%), fatigue (0.2%), and abdominal pain (0.2%).

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

Interactions

Drug Interactions
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
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Neratinib.
AbametapirThe serum concentration of Neratinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Neratinib can be increased when combined with Abatacept.
AcalabrutinibThe metabolism of Neratinib can be decreased when combined with Acalabrutinib.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Neratinib.
AcetazolamideThe metabolism of Neratinib can be decreased when combined with Acetazolamide.
AdalimumabThe metabolism of Neratinib can be increased when combined with Adalimumab.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Neratinib.
AlbendazoleThe metabolism of Neratinib can be decreased when combined with Albendazole.
AldesleukinThe metabolism of Neratinib can be decreased when combined with Aldesleukin.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of neratinib.
  • Exercise caution with St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of neratinib.
  • Take at the same time every day.
  • Take separate from antacids. Take antacids at least 3 hours before or after neratinib.
  • Take with food.

Products

Product Ingredients
IngredientUNIICASInChI Key
Neratinib Maleate9RM7XY23ZS915942-22-2VXZCUHNJXSIJIM-MEBGWEOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
NerlynxTablet40 mgOralKnight Therapeutics Inc.2019-12-20Not applicableCanada flag
NerlynxTablet40 mg/1OralPuma Biotechnology, Inc.2017-07-17Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01XE45 — Neratinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 4-aminoquinolines. These are organic compounds containing an amino group attached to the 4-position of a quinoline ring system.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Aminoquinolines and derivatives
Direct Parent
4-aminoquinolines
Alternative Parents
Aminophenyl ethers / Phenoxy compounds / N-arylamides / Aniline and substituted anilines / Alkyl aryl ethers / Aminopyridines and derivatives / Chlorobenzenes / Aryl chlorides / Heteroaromatic compounds / Trialkylamines
show 10 more
Substituents
4-aminoquinoline / Alkyl aryl ether / Amine / Amino acid or derivatives / Aminophenyl ether / Aminopyridine / Aniline or substituted anilines / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide
show 29 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
JJH94R3PWB
CAS number
698387-09-6
InChI Key
JWNPDZNEKVCWMY-VQHVLOKHSA-N
InChI
InChI=1S/C30H29ClN6O3/c1-4-39-28-16-25-23(15-26(28)36-29(38)9-7-13-37(2)3)30(20(17-32)18-34-25)35-21-10-11-27(24(31)14-21)40-19-22-8-5-6-12-33-22/h5-12,14-16,18H,4,13,19H2,1-3H3,(H,34,35)(H,36,38)/b9-7+
IUPAC Name
(2E)-N-[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
SMILES
CCOC1=C(NC(=O)\C=C\CN(C)C)C=C2C(NC3=CC=C(OCC4=CC=CC=N4)C(Cl)=C3)=C(C=NC2=C1)C#N

References

General References
Not Available
PubChem Compound
9915743
PubChem Substance
347828174
ChemSpider
8091392
BindingDB
50161957
RxNav
1940643
ChEBI
61397
ChEMBL
CHEMBL180022
ZINC
ZINC000003916214
Wikipedia
Neratinib
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (658 KB)
MSDS
Download (24 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentBreast Cancer1
3CompletedTreatmentHER2+ Metastatic Breast Cancer (MBC)1
2Active Not RecruitingTreatmentBreast Cancer1
2Active Not RecruitingTreatmentHER2 Positive Breast Carcinoma / Stage IV Breast Cancer AJCC v6 and v71
2CompletedTreatmentAdvanced Breast Cancer / Breast Cancer1
2CompletedTreatmentBreast Cancer2
2CompletedTreatmentHER2-mutant Non-Small Cell Lung Cancer1
2CompletedTreatmentNeoplasms, Lung / Non-Small Cell Lung Carcinoma (NSCLC)1
2CompletedTreatmentNeoplasms / Neoplasms, Breast1
2Not Yet RecruitingTreatmentBreast Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral40 mg/1
TabletOral40 mg
Tablet, film coatedOral40 MG
Tablet
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8790708No2014-07-292030-11-05US flag
US9139558No2015-09-222028-10-15US flag
US6288082No2001-09-112019-09-24US flag
US9211291No2015-12-152030-03-24US flag
US7982043No2011-07-192025-10-08US flag
US9630946No2017-04-252028-10-15US flag
US8518446No2013-08-272030-11-20US flag
US7399865No2008-07-152025-12-29US flag
US10035788No2018-07-312028-10-15US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00674 mg/mLALOGPS
logP4.72ALOGPS
logP4.47ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)12.55ChemAxon
pKa (Strongest Basic)8.81ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area112.4 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity157.29 m3·mol-1ChemAxon
Polarizability58.1 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
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

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
Inhibits the tyrosine kinase activity of the receptor to prevent autophosphorylation.
General Function
Ubiquitin protein ligase binding
Specific Function
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TG...
Gene Name
EGFR
Uniprot ID
P00533
Uniprot Name
Epidermal growth factor receptor
Molecular Weight
134276.185 Da

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Trimethylamine monooxygenase activity
Specific Function
Involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. It N-oxygenates primary aliphatic alkylamines as well as secondary and tertiary amines. Plays an impor...
Gene Name
FMO3
Uniprot ID
P31513
Uniprot Name
Dimethylaniline monooxygenase [N-oxide-forming] 3
Molecular Weight
60032.975 Da

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
Kind
Protein group
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...

Components:

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 on October 20, 2016 14:51 / Updated on October 19, 2020 07:46

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