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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
AfatinibumNot AvailableNot Available
BIBW 2992Not AvailableNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Gilotriftablet, film coated30 mgoralBoehringer Ingelheim Pharmaceuticals, Inc.2013-07-12Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Gilotriftablet, film coated40 mgoralBoehringer Ingelheim Pharmaceuticals, Inc.2013-07-12Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Gilotriftablet, film coated20 mgoralBoehringer Ingelheim Pharmaceuticals, Inc.2013-07-12Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Giotriftablet20 mgoralBoehringer Ingelheim (Canada) Ltd LteeNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Giotriftablet30 mgoralBoehringer Ingelheim (Canada) Ltd LteeNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Giotriftablet40 mgoralBoehringer Ingelheim (Canada) Ltd LteeNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
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
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
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.
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 substrateNon-inhibitor0.7294
CYP450 2D6 substrateNon-inhibitor0.7625
CYP450 2C19 substrateNon-inhibitor0.5877
CYP450 3A4 substrateNon-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
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral20 mg
Tabletoral30 mg
Tabletoral40 mg
Tablet, film coatedoral20 mg
Tablet, film coatedoral30 mg
Tablet, film coatedoral40 mg
PricesNot Available
PatentsNot Available
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 Reference
  1. FDA label
External Links
ATC CodesL01XE13
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (427 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AbirateroneP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
AmiodaroneP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
AtorvastatinP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
CarbamazepineP-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib.
CarvedilolP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
ClarithromycinP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
CrizotinibP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
DarunavirP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
DipyridamoleP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
DronedaroneP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
EliglustatP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
FosphenytoinP-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib.
ItraconazoleP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
IvacaftorP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
LapatinibP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
LedipasvirP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
LomitapideP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
LopinavirP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
MefloquineP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
NefazodoneP-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib.
NilotinibP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
PhenobarbitalP-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib.
PhenytoinP-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib.
PorfimerPhotosensitizing Agents may enhance the photosensitizing effect of Porfimer.
PrimidoneP-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib.
ProgesteroneP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
PropranololP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
QuinidineP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
QuinineP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
RanolazineP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
ReserpineP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
RifampicinP-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib.
RitonavirP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
SaquinavirP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
SimeprevirP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
SulfisoxazoleP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
SunitinibP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
TamoxifenP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
TelaprevirP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
TipranavirP-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib.
VandetanibP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
VemurafenibP-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.
VerteporfinPhotosensitizing Agents may enhance the photosensitizing effect of Verteporfin.
VinblastineP-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib.
Food Interactions
  • When given with a high-fat meal, Cmax decreases by 50% and AUC by 39% relative to the fasted state.

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