Identification
- Summary
Neratinib is a protein kinase inhibitor used to treat breast cancer that over expresses the HER2 receptor.
- Brand Names
- Nerlynx
- Generic Name
- Neratinib
- DrugBank Accession Number
- DB11828
- Background
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
Structure for Neratinib (DB11828)
- 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].
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Adjunct therapy in treatment of Breast cancer •••••••••••• ••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- 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.
Target Actions Organism AEpidermal growth factor receptor inhibitorHumans - 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
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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%).
- 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 softwareAbametapir The serum concentration of Neratinib can be increased when it is combined with Abametapir. Abatacept The metabolism of Neratinib can be increased when combined with Abatacept. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Neratinib. Acalabrutinib The metabolism of Neratinib can be decreased when combined with Acalabrutinib. Acetaminophen The metabolism of Neratinib can be increased when combined with Acetaminophen. - 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
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.- Product Ingredients
Ingredient UNII CAS InChI Key Neratinib maleate 9RM7XY23ZS 915942-22-2 VXZCUHNJXSIJIM-MEBGWEOYSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Nerlynx Tablet 40 mg/1 Oral Puma Biotechnology, Inc. 2017-07-17 Not applicable US 
Nerlynx Tablet, film coated 40 mg Oral Pierre Fabre Médicament 2020-12-16 Not applicable EU 
Nerlynx Tablet 40 mg Oral Knight Therapeutics Inc. 2019-12-20 Not applicable Canada 
Categories
- ATC Codes
- L01EH02 — Neratinib
- Drug Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Substrates
- Enzyme Inhibitors
- Heterocyclic Compounds, Fused-Ring
- Human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitors
- Kinase Inhibitor
- Narrow Therapeutic Index Drugs
- P-glycoprotein inhibitors
- Protein Kinase Inhibitors
- Tyrosine Kinase Inhibitors
- 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
- Affected organisms
- Humans and other mammals
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
- External Links
- PubChem Compound
- 9915743
- PubChem Substance
- 347828174
- ChemSpider
- 8091392
- BindingDB
- 50161957
- 1940643
- ChEBI
- 61397
- ChEMBL
- CHEMBL180022
- ZINC
- ZINC000003916214
- Wikipedia
- Neratinib
- FDA label
- Download (658 KB)
- MSDS
- Download (24 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 3 Completed Treatment Breast Cancer 1 3 Completed Treatment HER2+ Metastatic Breast Cancer (MBC) 1 3 Not Yet Recruiting Treatment Biliary Tract Neoplasms 1 2 Active Not Recruiting Treatment Breast Cancer 1 2 Active Not Recruiting Treatment HER2 Gene Mutation / Metastatic Cancer 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 40 mg Tablet Oral 40 mg/1 Tablet, film coated Oral 40 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8790708 No 2014-07-29 2030-11-05 US US9139558 No 2015-09-22 2028-10-15 US US6288082 No 2001-09-11 2019-09-24 US US9211291 No 2015-12-15 2030-03-24 US US7982043 No 2011-07-19 2025-10-08 US US9630946 No 2017-04-25 2028-10-15 US US8518446 No 2013-08-27 2030-11-20 US US7399865 No 2008-07-15 2025-12-29 US US10035788 No 2018-07-31 2028-10-15 US US9265784 No 2016-02-23 2029-08-04 US US8669273 No 2014-03-11 2031-07-18 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00674 mg/mL ALOGPS logP 4.72 ALOGPS logP 4.47 Chemaxon logS -4.9 ALOGPS pKa (Strongest Acidic) 12.55 Chemaxon pKa (Strongest Basic) 8.81 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 8 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 112.4 Å2 Chemaxon Rotatable Bond Count 11 Chemaxon Refractivity 157.29 m3·mol-1 Chemaxon Polarizability 58.1 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No 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]- 225.68922 predictedDeepCCS 1.0 (2019) [M+H]+ 228.0848 predictedDeepCCS 1.0 (2019) [M+Na]+ 233.99733 predictedDeepCCS 1.0 (2019)
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 at October 20, 2016 20:51 / Updated at December 05, 2023 12:31