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Identification
NameAfatinib
Accession NumberDB08916
Typesmall molecule
Groupsapproved
Description

Afatinib is a tyrosine kinase inhibitor which is a 4-anilinoquinazoline. It is prepared has the dimaleate salt. FDA approved on July 12, 2013.

Structure
Thumb
Synonyms
SynonymLanguageCode
BIBW 2992Not AvailableNot Available
Salts
Name/CAS Structure Properties
Afatinib Dimaleate
Thumb
  • InChI Key: USNRYVNRPYXCSP-JUGPPOIOSA-N
  • Monoisotopic Mass: 717.184912835
  • Average Mass: 718.083
DBSALT000005
Brand names
NameCompany
GilotrifBoehringer Ingelheim
Brand mixturesNot Available
CategoriesNot Available
CAS number850140-72-6
WeightAverage: 485.938
Monoisotopic: 485.162995603
Chemical FormulaC24H25ClFN5O3
InChI KeyULXXDDBFHOBEHA-CWDCEQMOSA-N
InChI
InChI=1S/C24H25ClFN5O3/c1-31(2)8-3-4-23(32)30-21-11-17-20(12-22(21)34-16-7-9-33-13-16)27-14-28-24(17)29-15-5-6-19(26)18(25)10-15/h3-6,10-12,14,16H,7-9,13H2,1-2H3,(H,30,32)(H,27,28,29)/b4-3+/t16-/m0/s1
IUPAC Name
(2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[(3S)-oxolan-3-yloxy]quinazolin-6-yl}-4-(dimethylamino)but-2-enamide
SMILES
CN(C)C\C=C\C(=O)NC1=C(O[C@H]2CCOC2)C=C2N=CN=C(NC3=CC(Cl)=C(F)C=C3)C2=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassNaphthyridines
SubclassQuinazolines
Direct parentQuinazolinamines
Alternative parentsAnilides; Phenol Ethers; Aminopyrimidines and Derivatives; Chlorobenzenes; Alkyl Aryl Ethers; Fluorobenzenes; Aryl Chlorides; Aryl Fluorides; Oxolanes; Enones; Tetrahydrofurans; Tertiary Amines; Secondary Carboxylic Acid Amides; Carboxylic Acids; Polyamines; Enolates; Secondary Amines; Organofluorides; Organochlorides
Substituentsphenol ether; fluorobenzene; aminopyrimidine; alkyl aryl ether; chlorobenzene; aryl halide; aryl fluoride; benzene; aryl chloride; pyrimidine; tetrahydrofuran; enone; oxolane; secondary carboxylic acid amide; tertiary amine; carboxamide group; polyamine; ether; enolate; secondary amine; carboxylic acid; carboxylic acid derivative; amine; organochloride; organohalogen; organonitrogen compound; organofluoride
Classification descriptionThis compound belongs to the quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
Pharmacology
IndicationAfatinib is a kinase inhibitor indicated for the first-line treatment of patient with metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
PharmacodynamicsAfatinib did not effect the QTc interval.
Mechanism of actionAfatinib is an irreversible kinase inhibitor and binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) to inhibit tyrosine kinase autophosphorylation. This results in a downregulation of ErbB signalling and subsequent inhibition of proliferation of cell lines expressing wild-type EGFR, selected EGFR exon 19 deletion mutations, or exon 21 L858R mutations. It also inhibited in vitro proliferation of cell lines overexpressing HER2. Overall, tumour growth was inhibited.
AbsorptionFollowing oral administration, time to peak plasma concentration (Tmax) is 2 to 5 hours. The geometric mean relative bioavailability of 20 mg tablets was 92% as compared to an oral solution. Food decreases Cmax and AUC relative to the fasted state.
Volume of distributionNot Available
Protein binding95% bound to human plasma protein.
Metabolism

Enzymatic metabolism of afatinib is minimal. Covalent adducts to proteins are the major circulating metabolites.

Route of eliminationExcretion of afatinib is primarily via the feces (85%), with 4% recovered in the urine following a single oral dose of afatinib solution. The parent compound accounted for 88% of the recovered dose.
Half lifeCancer patients, repeat dosing = 37 hours
ClearanceNot Available
ToxicityMost common adverse reactions (≥20%) are diarrhea, rash/dermatitis, acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated Effects
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeEffectReference(s)
Epidermal growth factor receptor
Gene symbol: EGFR
UniProt: P00533
Not AvailableG719A/C OR (L858R and L861Q)Not AvailableAssociated with enhanced activation of the EGFR tyrosine kinase in patients with non-small cell lung cancer (NSCLC) recieving tyrosine kinase inhibitor therapy.15118073
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.8717
Caco-2 permeable - 0.5342
P-glycoprotein substrate Substrate 0.744
P-glycoprotein inhibitor I Inhibitor 0.6776
P-glycoprotein inhibitor II Inhibitor 0.9036
Renal organic cation transporter Non-inhibitor 0.7154
CYP450 2C9 substrate Non-substrate 0.7919
CYP450 2D6 substrate Non-substrate 0.8034
CYP450 3A4 substrate Substrate 0.7504
CYP450 1A2 substrate Non-inhibitor 0.5236
CYP450 2C9 substrate Non-inhibitor 0.7294
CYP450 2D6 substrate Non-inhibitor 0.7625
CYP450 2C19 substrate Non-inhibitor 0.5877
CYP450 3A4 substrate Non-inhibitor 0.6486
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7096
Ames test Non AMES toxic 0.5695
Carcinogenicity Non-carcinogens 0.8692
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.5643 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8956
hERG inhibition (predictor II) Inhibitor 0.7228
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral20 mg, 30 mg, 40 mg
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
water solubility1.28e-02 g/lALOGPS
logP3.77ALOGPS
logP3.76ChemAxon
logS-4.6ALOGPS
pKa (strongest acidic)12.49ChemAxon
pKa (strongest basic)8.81ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count7ChemAxon
hydrogen donor count2ChemAxon
polar surface area88.61ChemAxon
rotatable bond count8ChemAxon
refractivity131.38ChemAxon
polarizability50.07ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. FDA label
External Links
ResourceLink
KEGG DrugD09724
Drugs.comhttp://www.drugs.com/gilotrif.html
WikipediaAfatinib
ATC CodesL01XE13
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelshow(427 KB)
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Epidermal growth factor receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Epidermal growth factor receptor P00533 Details

References:

  1. FDA label

2. Receptor tyrosine-protein kinase erbB-2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Receptor tyrosine-protein kinase erbB-2 P04626 Details

References:

  1. FDA label

3. Receptor tyrosine-protein kinase erbB-4

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Receptor tyrosine-protein kinase erbB-4 Q15303 Details

References:

  1. FDA label

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. FDA label

2. ATP-binding cassette sub-family G member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 2 Q9UNQ0 Details

References:

  1. FDA label

Comments
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Drug created on July 17, 2013 15:59 / Updated on September 16, 2013 18:11