You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
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
Afatinibum
BIBW 2992
External Identifiers Not Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Gilotriftablet, film coated30 mg/1oralBoehringer Ingelheim Pharmaceuticals, Inc.2013-07-122016-04-23Us
Gilotriftablet, film coated20 mg/1oralBoehringer Ingelheim Pharmaceuticals, Inc.2013-07-122016-04-23Us
Gilotriftablet, film coated40 mg/1oralBoehringer Ingelheim Pharmaceuticals, Inc.2013-07-122016-04-23Us
Giotriftablet40 mgoralBoehringer Ingelheim (Canada) Ltd Ltee2014-01-17Not applicableCanada
Giotriftablet30 mgoralBoehringer Ingelheim (Canada) Ltd Ltee2014-01-17Not applicableCanada
Giotriftablet20 mgoralBoehringer Ingelheim (Canada) Ltd Ltee2014-01-17Not applicableCanada
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Afatinib Dimaleate
Thumb
  • InChI Key: USNRYVNRPYXCSP-JUGPPOIOSA-N
  • Monoisotopic Mass: 717.184912835
  • Average Mass: 718.083
DBSALT000005
Categories
UNII41UD74L59M
CAS number850140-72-6
WeightAverage: 485.938
Monoisotopic: 485.162995603
Chemical FormulaC24H25ClFN5O3
InChI KeyInChIKey=ULXXDDBFHOBEHA-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[[email protected]]2CCOC2)C=C2N=CN=C(NC3=CC(Cl)=C(F)C=C3)C2=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassNaphthyridines
Sub ClassQuinazolines
Direct ParentQuinazolinamines
Alternative Parents
Substituents
  • Quinazolinamine
  • N-arylamide
  • Halobenzene
  • Fluorobenzene
  • Chlorobenzene
  • Aminopyrimidine
  • Alkyl aryl ether
  • Imidolactam
  • Benzenoid
  • Pyrimidine
  • Saccharide
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl fluoride
  • Aryl chloride
  • Heteroaromatic compound
  • Oxolane
  • Tertiary aliphatic amine
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Carboxamide group
  • Oxacycle
  • Azacycle
  • Secondary amine
  • Ether
  • Dialkyl ether
  • Carboxylic acid derivative
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organochloride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
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.
Related Articles
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
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.8717
Caco-2 permeable-0.5342
P-glycoprotein substrateSubstrate0.744
P-glycoprotein inhibitor IInhibitor0.6776
P-glycoprotein inhibitor IIInhibitor0.9036
Renal organic cation transporterNon-inhibitor0.7154
CYP450 2C9 substrateNon-substrate0.7919
CYP450 2D6 substrateNon-substrate0.8034
CYP450 3A4 substrateSubstrate0.7504
CYP450 1A2 substrateNon-inhibitor0.5236
CYP450 2C9 inhibitorNon-inhibitor0.7294
CYP450 2D6 inhibitorNon-inhibitor0.7625
CYP450 2C19 inhibitorNon-inhibitor0.5877
CYP450 3A4 inhibitorNon-inhibitor0.6486
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7096
Ames testNon AMES toxic0.5695
CarcinogenicityNon-carcinogens0.8692
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5643 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8956
hERG inhibition (predictor II)Inhibitor0.7228
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tablet, film coatedoral20 mg/1
Tablet, film coatedoral30 mg/1
Tablet, film coatedoral40 mg/1
Tabletoral20 mg
Tabletoral30 mg
Tabletoral40 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6251912 No1998-07-292018-07-29Us
US8426586 No2009-10-102029-10-10Us
US8545884 No2009-12-192029-12-19Us
USRE43431 No2002-01-222022-01-22Us
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0128 mg/mLALOGPS
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 Area88.61 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity131.38 m3·mol-1ChemAxon
Polarizability50.07 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. FDA label
External Links
ATC CodesL01XE13
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (427 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AbirateroneThe serum concentration of Afatinib can be increased when it is combined with Abiraterone.
AmiodaroneThe serum concentration of Afatinib can be increased when it is combined with Amiodarone.
AtorvastatinThe serum concentration of Afatinib can be increased when it is combined with Atorvastatin.
AzithromycinThe serum concentration of Afatinib can be increased when it is combined with Azithromycin.
CarbamazepineThe serum concentration of Afatinib can be decreased when it is combined with Carbamazepine.
CarvedilolThe serum concentration of Afatinib can be increased when it is combined with Carvedilol.
ClarithromycinThe serum concentration of Afatinib can be increased when it is combined with Clarithromycin.
CobicistatThe serum concentration of Afatinib can be increased when it is combined with Cobicistat.
CrizotinibThe serum concentration of Afatinib can be increased when it is combined with Crizotinib.
CyclosporineThe serum concentration of Afatinib can be increased when it is combined with Cyclosporine.
DaclatasvirThe serum concentration of Afatinib can be increased when it is combined with Daclatasvir.
DarunavirThe serum concentration of Afatinib can be increased when it is combined with Darunavir.
DipyridamoleThe serum concentration of Afatinib can be increased when it is combined with Dipyridamole.
DronedaroneThe serum concentration of Afatinib can be increased when it is combined with Dronedarone.
EliglustatThe serum concentration of Afatinib can be increased when it is combined with Eliglustat.
ErythromycinThe serum concentration of Afatinib can be increased when it is combined with Erythromycin.
FlibanserinThe serum concentration of Afatinib can be increased when it is combined with Flibanserin.
FosphenytoinThe serum concentration of Afatinib can be decreased when it is combined with Fosphenytoin.
IbrutinibThe serum concentration of Afatinib can be increased when it is combined with Ibrutinib.
ItraconazoleThe serum concentration of Afatinib can be increased when it is combined with Itraconazole.
IvacaftorThe serum concentration of Afatinib can be increased when it is combined with Ivacaftor.
KetoconazoleThe serum concentration of Afatinib can be increased when it is combined with Ketoconazole.
LapatinibThe serum concentration of Afatinib can be increased when it is combined with Lapatinib.
LomitapideThe serum concentration of Afatinib can be increased when it is combined with Lomitapide.
LumacaftorThe serum concentration of Afatinib can be decreased when it is combined with Lumacaftor.
MefloquineThe serum concentration of Afatinib can be increased when it is combined with Mefloquine.
MirabegronThe serum concentration of Afatinib can be increased when it is combined with Mirabegron.
NicardipineThe serum concentration of Afatinib can be increased when it is combined with Nicardipine.
NilotinibThe serum concentration of Afatinib can be increased when it is combined with Nilotinib.
PhenobarbitalThe serum concentration of Afatinib can be decreased when it is combined with Phenobarbital.
PhenytoinThe serum concentration of Afatinib can be decreased when it is combined with Phenytoin.
PorfimerAfatinib may increase the photosensitizing activities of Porfimer.
PrimidoneThe serum concentration of Afatinib can be decreased when it is combined with Primidone.
ProgesteroneThe serum concentration of Afatinib can be increased when it is combined with Progesterone.
PropranololThe serum concentration of Afatinib can be increased when it is combined with Propranolol.
QuinidineThe serum concentration of Afatinib can be increased when it is combined with Quinidine.
QuinineThe serum concentration of Afatinib can be increased when it is combined with Quinine.
RanolazineThe serum concentration of Afatinib can be increased when it is combined with Ranolazine.
ReserpineThe serum concentration of Afatinib can be increased when it is combined with Reserpine.
RifampicinThe serum concentration of Afatinib can be decreased when it is combined with Rifampicin.
RitonavirThe serum concentration of Afatinib can be increased when it is combined with Ritonavir.
RolapitantThe serum concentration of Afatinib can be increased when it is combined with Rolapitant.
SaquinavirThe serum concentration of Afatinib can be increased when it is combined with Saquinavir.
SimeprevirThe serum concentration of Afatinib can be increased when it is combined with Simeprevir.
SunitinibThe serum concentration of Afatinib can be increased when it is combined with Sunitinib.
TacrolimusThe serum concentration of Afatinib can be increased when it is combined with Tacrolimus.
TamoxifenThe serum concentration of Afatinib can be increased when it is combined with Tamoxifen.
TelaprevirThe serum concentration of Afatinib can be increased when it is combined with Telaprevir.
TesmilifeneThe serum concentration of Afatinib can be decreased when it is combined with Tesmilifene.
TipranavirThe serum concentration of Afatinib can be decreased when it is combined with Tipranavir.
VandetanibThe serum concentration of Afatinib can be increased when it is combined with Vandetanib.
VemurafenibThe serum concentration of Afatinib can be increased when it is combined with Vemurafenib.
VerapamilThe serum concentration of Afatinib can be increased when it is combined with Verapamil.
VerteporfinAfatinib may increase the photosensitizing activities of Verteporfin.
VinblastineThe serum concentration of Afatinib can be decreased when it is combined with Vinblastine.
Food Interactions
  • When given with a high-fat meal, Cmax decreases by 50% and AUC by 39% relative to the fasted state.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
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, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on ke...
Gene Name:
EGFR
Uniprot ID:
P00533
Molecular Weight:
134276.185 Da
References
  1. FDA label
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Transmembrane signaling receptor activity
Specific Function:
Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-...
Gene Name:
ERBB2
Uniprot ID:
P04626
Molecular Weight:
137909.27 Da
References
  1. FDA label
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Transmembrane receptor protein tyrosine kinase activity
Specific Function:
Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyo...
Gene Name:
ERBB4
Uniprot ID:
Q15303
Molecular Weight:
146806.865 Da
References
  1. FDA label

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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
Molecular Weight:
141477.255 Da
References
  1. FDA label
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from t...
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
Molecular Weight:
72313.47 Da
References
  1. FDA label
Comments
comments powered by Disqus
Drug created on July 17, 2013 15:59 / Updated on May 04, 2016 02:30