U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C24H25ClFN5O3
Molecular Weight 485.9393
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of AFATINIB

SMILES

CN(C)C/C(/[H])=C(\[H])/C(=Nc1cc2c(cc1O[C@@]3([H])CCOC3)ncnc2Nc4ccc(c(c4)Cl)F)O

InChI

InChIKey=ULXXDDBFHOBEHA-CWDCEQMOSA-N
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

HIDE SMILES / InChI

Molecular Formula C24H25ClFN5O3
Molecular Weight 485.9393
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 1
Optical Activity UNSPECIFIED

Description
Curator's Comment:: description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000PharmR.pdf

Afatinib is a anilino-quinazoline derivative and irreversible antagonist of the receptor tyrosine kinase epidermal growth factor receptor family, with antineoplastic activity. Afatinib selectively and covalently binds to and inhibits the epidermal growth factor receptors 1 (ErbB1; EGFR), 2 (ErbB2; HER2), and 4 (ErbB4; HER4), and certain EGFR mutants, including those caused by EGFR exon 19 deletion mutations or exon 21 (L858R) mutations. This may result in the inhibition of tumor growth and angiogenesis in tumor cells overexpressing these kinases. Additionally, afatinib inhibits the EGFR T790M gatekeeper mutation which is resistant to treatment with first-generation EGFR inhibitors. EGFR, HER2 and HER4 are RTKs that belong to the EGFR superfamily; they play major roles in both tumor cell proliferation and tumor vascularization and are overexpressed in many cancer cell types. Afatinib is a substrate and an inhibitor of P-gp and of the transporter BCRP. Co-administration of P-gp inhibitors can increase afatinib exposure while co-administration of chronic P­gp inducers can decrease afatinib exposure.

CNS Activity

Curator's Comment:: Afatinib appears to penetrate into the CNS with concentrations high enough to have clinical effect on CNS metastases

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: P00533|||Q9GZX1
Gene ID: 1956.0
Gene Symbol: EGFR
Target Organism: Homo sapiens (Human)
0.5 nM [IC50]
Target ID: P04626
Gene ID: 2064.0
Gene Symbol: ERBB2
Target Organism: Homo sapiens (Human)
14.0 nM [IC50]
Target ID: Q15303
Gene ID: 2066.0
Gene Symbol: ERBB4
Target Organism: Homo sapiens (Human)
0.7 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
GILOTRIF

Approved Use

Indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test

Launch Date

1.37358724E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
42.7 ng/mL
40 mg 1 times / day steady-state, oral
dose: 40 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
AFATINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
33.7 ng/mL
50 mg single, oral
dose: 50 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
AFATINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: MALE
food status: FASTED
30.7 ng/mL
50 mg single, oral
dose: 50 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
AFATINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
683 ng × h/mL
40 mg 1 times / day steady-state, oral
dose: 40 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
AFATINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
886 ng × h/mL
50 mg single, oral
dose: 50 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
AFATINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: MALE
food status: FASTED
956 ng × h/mL
50 mg single, oral
dose: 50 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
AFATINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
74.9 h
50 mg single, oral
dose: 50 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
AFATINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: MALE
food status: FASTED
60.3 h
50 mg single, oral
dose: 50 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
AFATINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
5%
AFATINIB plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Other AEs: Diarrhoea, Rash...
Other AEs:
Diarrhoea (84.6%)
Rash (72.3%)
Dermatitis acneiform (13.6%)
Stomatitis (58.2%)
Nail disorder (38.5%)
Decreased appetite (20.8%)
Nausea (18.7%)
Pruritus (17.7%)
Epistaxis (14.6%)
Dry skin (14.4%)
Fatigue (14.4%)
Vomiting (13.3%)
Eye disorders NEC (9.2%)
Palmar-plantar erythrodysaesthesia syndrome (7.7%)
Diarrhoea (grade 3, 38.7%)
Rash (grade 3, 13.3%)
Dermatitis acneiform (grade 3, 1.3%)
Stomatitis (grade 3, 2.8%)
Nail disorder (grade 3, 4.9%)
Decreased appetite (grade 3, 2.8%)
Nausea (grade 3, 1.3%)
Pruritus (grade 3, 0.3%)
Dry skin (grade 3, 0.3%)
Fatigue (grade 3, 3.1%)
Vomiting (grade 3, 1.5%)
Eye disorders NEC (grade 3, 0.5%)
Palmar-plantar erythrodysaesthesia syndrome (grade 3, 1.3%)
Diarrhoea (grade 4, 1%)
Sources:
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Other AEs: ALT increased, AST increased...
Other AEs:
ALT increased (3.8%)
AST increased (2.8%)
Alkaline phosphatase increased (0.8%)
Bilirubin increased (0.3%)
GGT increased (0.3%)
Hyperbilirubinaemia (1%)
Hypoalbuminaemia (1.5%)
Acute hepatic failure (0.3%)
Anorectal varices (0.3%)
Cytolytic hepatitis (0.3%)
Hepatic pain (0.3%)
Hepatitis acute (0.3%)
Sources:
360 mg 1 times / day single, oral
Dose: 360 mg, 1 times / day
Route: oral
Route: single
Dose: 360 mg, 1 times / day
Sources:
healthy, adolescents
n = 2
Health Status: healthy
Age Group: adolescents
Population Size: 2
Sources:
Other AEs: Nausea, Vomiting...
Other AEs:
Nausea
Vomiting
Asthenia
Dizziness
Headache
Abdominal pain
Amylase increased
Sources:
100 mg 1 times / day multiple, oral
Highest studied dose
Dose: 100 mg, 1 times / day
Route: oral
Route: multiple
Dose: 100 mg, 1 times / day
Sources:
unhealthy, median age 58 years
n = 2
Health Status: unhealthy
Condition: solid tumours
Age Group: median age 58 years
Sex: M+F
Population Size: 2
Sources:
DLT: Skin rash, Diarrhoea...
Dose limiting toxicities:
Skin rash (grade 3, 50%)
Diarrhoea (grade 3, 50%)
Sources:
70 mg 1 times / day multiple, oral
MTD
Dose: 70 mg, 1 times / day
Route: oral
Route: multiple
Dose: 70 mg, 1 times / day
Sources:
unhealthy, median age 58 years
n = 18
Health Status: unhealthy
Condition: solid tumours
Age Group: median age 58 years
Sex: M+F
Population Size: 18
Sources:
DLT: Fatigue, ALT increased...
Dose limiting toxicities:
Fatigue (grade 3, 5.6%)
ALT increased (grade 3, 5.6%)
Sources:
70 mg 1 times / day multiple, oral
Dose: 70 mg, 1 times / day
Route: oral
Route: multiple
Dose: 70 mg, 1 times / day
Sources:
unhealthy, median age 58 years
n = 18
Health Status: unhealthy
Condition: solid tumours
Age Group: median age 58 years
Sex: M+F
Population Size: 18
Sources:
DLT: Diarrhoea...
Dose limiting toxicities:
Diarrhoea (grade 3, 11.1%)
Sources:
85 mg 1 times / day multiple, oral
Dose: 85 mg, 1 times / day
Route: oral
Route: multiple
Dose: 85 mg, 1 times / day
Sources:
unhealthy, median age 58 years
n = 6
Health Status: unhealthy
Condition: solid tumours
Age Group: median age 58 years
Sex: M+F
Population Size: 6
Sources:
DLT: Diarrhoea, Diarrhoea...
Dose limiting toxicities:
Diarrhoea (grade 3, 16.7%)
Diarrhoea (grade 2, 16.7%)
Sources:
40 mg 1 times / day multiple, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: multiple
Dose: 40 mg, 1 times / day
Sources:
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Disc. AE: Diarrhea, Paronychia...
AEs leading to
discontinuation/dose reduction:
Diarrhea (1.3%)
Paronychia (0.9%)
Interstitial lung disease (1%)
Sources:
40 mg 1 times / day multiple, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: multiple
Dose: 40 mg, 1 times / day
Sources:
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Other AEs: Diarrhea, Stomatitis...
40 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Other AEs: Weight decreased, Nausea...
Other AEs:
Weight decreased (grade 3, 1%)
Nausea (grade 3, 1%)
Vomiting (grade 3, 4%)
Dermatitis acneiform (grade 3, 3%)
Hypokalaemia (grade 3, 2%)
ALT increased (grade 3, 2%)
AST increased (grade 3, 2%)
Stomatitis (grade 4, <1%)
Hypokalaemia (grade 4, 2%)
Sources:
40 mg 1 times / day multiple, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: multiple
Dose: 40 mg, 1 times / day
Sources: Page: 201292Orig1s000MedR.pdf - p.66
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources: Page: 201292Orig1s000MedR.pdf - p.66
Other AEs: Rash, Paronychia...
Other AEs:
Rash (grade 3, 16%)
Paronychia (grade 3, 11%)
Cystitis (grade 3, 1%)
Decreased appetite (grade 3, 4%)
Sources: Page: 201292Orig1s000MedR.pdf - p.66
AEs

AEs

AESignificanceDosePopulation
Vomiting 13.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Dermatitis acneiform 13.6%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Dry skin 14.4%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Fatigue 14.4%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Epistaxis 14.6%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Pruritus 17.7%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Nausea 18.7%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Decreased appetite 20.8%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Nail disorder 38.5%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Stomatitis 58.2%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Palmar-plantar erythrodysaesthesia syndrome 7.7%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Rash 72.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Diarrhoea 84.6%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Eye disorders NEC 9.2%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Dry skin grade 3, 0.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Pruritus grade 3, 0.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Eye disorders NEC grade 3, 0.5%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Dermatitis acneiform grade 3, 1.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Nausea grade 3, 1.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Palmar-plantar erythrodysaesthesia syndrome grade 3, 1.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Vomiting grade 3, 1.5%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Rash grade 3, 13.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Decreased appetite grade 3, 2.8%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Stomatitis grade 3, 2.8%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Fatigue grade 3, 3.1%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Diarrhoea grade 3, 38.7%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Nail disorder grade 3, 4.9%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Diarrhoea grade 4, 1%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Acute hepatic failure 0.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Anorectal varices 0.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Bilirubin increased 0.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Cytolytic hepatitis 0.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
GGT increased 0.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Hepatic pain 0.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Hepatitis acute 0.3%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Alkaline phosphatase increased 0.8%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Hyperbilirubinaemia 1%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Hypoalbuminaemia 1.5%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
AST increased 2.8%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
ALT increased 3.8%
50 mg 1 times / day multiple, oral
unhealthy, 32 to 82 years
n = 390
Health Status: unhealthy
Condition: non-small cell lung cancer
Age Group: 32 to 82 years
Sex: M+F
Population Size: 390
Sources:
Abdominal pain
360 mg 1 times / day single, oral
Dose: 360 mg, 1 times / day
Route: oral
Route: single
Dose: 360 mg, 1 times / day
Sources:
healthy, adolescents
n = 2
Health Status: healthy
Age Group: adolescents
Population Size: 2
Sources:
Amylase increased
360 mg 1 times / day single, oral
Dose: 360 mg, 1 times / day
Route: oral
Route: single
Dose: 360 mg, 1 times / day
Sources:
healthy, adolescents
n = 2
Health Status: healthy
Age Group: adolescents
Population Size: 2
Sources:
Asthenia
360 mg 1 times / day single, oral
Dose: 360 mg, 1 times / day
Route: oral
Route: single
Dose: 360 mg, 1 times / day
Sources:
healthy, adolescents
n = 2
Health Status: healthy
Age Group: adolescents
Population Size: 2
Sources:
Dizziness
360 mg 1 times / day single, oral
Dose: 360 mg, 1 times / day
Route: oral
Route: single
Dose: 360 mg, 1 times / day
Sources:
healthy, adolescents
n = 2
Health Status: healthy
Age Group: adolescents
Population Size: 2
Sources:
Headache
360 mg 1 times / day single, oral
Dose: 360 mg, 1 times / day
Route: oral
Route: single
Dose: 360 mg, 1 times / day
Sources:
healthy, adolescents
n = 2
Health Status: healthy
Age Group: adolescents
Population Size: 2
Sources:
Nausea
360 mg 1 times / day single, oral
Dose: 360 mg, 1 times / day
Route: oral
Route: single
Dose: 360 mg, 1 times / day
Sources:
healthy, adolescents
n = 2
Health Status: healthy
Age Group: adolescents
Population Size: 2
Sources:
Vomiting
360 mg 1 times / day single, oral
Dose: 360 mg, 1 times / day
Route: oral
Route: single
Dose: 360 mg, 1 times / day
Sources:
healthy, adolescents
n = 2
Health Status: healthy
Age Group: adolescents
Population Size: 2
Sources:
Diarrhoea grade 3, 50%
DLT
100 mg 1 times / day multiple, oral
Highest studied dose
Dose: 100 mg, 1 times / day
Route: oral
Route: multiple
Dose: 100 mg, 1 times / day
Sources:
unhealthy, median age 58 years
n = 2
Health Status: unhealthy
Condition: solid tumours
Age Group: median age 58 years
Sex: M+F
Population Size: 2
Sources:
Skin rash grade 3, 50%
DLT
100 mg 1 times / day multiple, oral
Highest studied dose
Dose: 100 mg, 1 times / day
Route: oral
Route: multiple
Dose: 100 mg, 1 times / day
Sources:
unhealthy, median age 58 years
n = 2
Health Status: unhealthy
Condition: solid tumours
Age Group: median age 58 years
Sex: M+F
Population Size: 2
Sources:
ALT increased grade 3, 5.6%
DLT
70 mg 1 times / day multiple, oral
MTD
Dose: 70 mg, 1 times / day
Route: oral
Route: multiple
Dose: 70 mg, 1 times / day
Sources:
unhealthy, median age 58 years
n = 18
Health Status: unhealthy
Condition: solid tumours
Age Group: median age 58 years
Sex: M+F
Population Size: 18
Sources:
Fatigue grade 3, 5.6%
DLT
70 mg 1 times / day multiple, oral
MTD
Dose: 70 mg, 1 times / day
Route: oral
Route: multiple
Dose: 70 mg, 1 times / day
Sources:
unhealthy, median age 58 years
n = 18
Health Status: unhealthy
Condition: solid tumours
Age Group: median age 58 years
Sex: M+F
Population Size: 18
Sources:
Diarrhoea grade 3, 11.1%
DLT
70 mg 1 times / day multiple, oral
Dose: 70 mg, 1 times / day
Route: oral
Route: multiple
Dose: 70 mg, 1 times / day
Sources:
unhealthy, median age 58 years
n = 18
Health Status: unhealthy
Condition: solid tumours
Age Group: median age 58 years
Sex: M+F
Population Size: 18
Sources:
Diarrhoea grade 2, 16.7%
DLT
85 mg 1 times / day multiple, oral
Dose: 85 mg, 1 times / day
Route: oral
Route: multiple
Dose: 85 mg, 1 times / day
Sources:
unhealthy, median age 58 years
n = 6
Health Status: unhealthy
Condition: solid tumours
Age Group: median age 58 years
Sex: M+F
Population Size: 6
Sources:
Diarrhoea grade 3, 16.7%
DLT
85 mg 1 times / day multiple, oral
Dose: 85 mg, 1 times / day
Route: oral
Route: multiple
Dose: 85 mg, 1 times / day
Sources:
unhealthy, median age 58 years
n = 6
Health Status: unhealthy
Condition: solid tumours
Age Group: median age 58 years
Sex: M+F
Population Size: 6
Sources:
Paronychia 0.9%
Disc. AE
40 mg 1 times / day multiple, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: multiple
Dose: 40 mg, 1 times / day
Sources:
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Interstitial lung disease 1%
Disc. AE
40 mg 1 times / day multiple, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: multiple
Dose: 40 mg, 1 times / day
Sources:
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Diarrhea 1.3%
Disc. AE
40 mg 1 times / day multiple, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: multiple
Dose: 40 mg, 1 times / day
Sources:
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Diarrhea grade 3, 15%
40 mg 1 times / day multiple, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: multiple
Dose: 40 mg, 1 times / day
Sources:
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Stomatitis grade 3, 8%
40 mg 1 times / day multiple, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: multiple
Dose: 40 mg, 1 times / day
Sources:
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Nausea grade 3, 1%
40 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Weight decreased grade 3, 1%
40 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
ALT increased grade 3, 2%
40 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
AST increased grade 3, 2%
40 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Hypokalaemia grade 3, 2%
40 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Dermatitis acneiform grade 3, 3%
40 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Vomiting grade 3, 4%
40 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Hypokalaemia grade 4, 2%
40 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Stomatitis grade 4, <1%
40 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources:
Cystitis grade 3, 1%
40 mg 1 times / day multiple, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: multiple
Dose: 40 mg, 1 times / day
Sources: Page: 201292Orig1s000MedR.pdf - p.66
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources: Page: 201292Orig1s000MedR.pdf - p.66
Paronychia grade 3, 11%
40 mg 1 times / day multiple, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: multiple
Dose: 40 mg, 1 times / day
Sources: Page: 201292Orig1s000MedR.pdf - p.66
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources: Page: 201292Orig1s000MedR.pdf - p.66
Rash grade 3, 16%
40 mg 1 times / day multiple, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: multiple
Dose: 40 mg, 1 times / day
Sources: Page: 201292Orig1s000MedR.pdf - p.66
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources: Page: 201292Orig1s000MedR.pdf - p.66
Decreased appetite grade 3, 4%
40 mg 1 times / day multiple, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: multiple
Dose: 40 mg, 1 times / day
Sources: Page: 201292Orig1s000MedR.pdf - p.66
unhealthy, median age 61.5 years
n = 229
Health Status: unhealthy
Condition: adenocarcinoma of the lung
Age Group: median age 61.5 years
Sex: M+F
Population Size: 229
Sources: Page: 201292Orig1s000MedR.pdf - p.66
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
yes [IC50 0.75 uM]
yes [Ki 3.4 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
minor
yes [Km 30 uM]
yes (co-administration study)
Comment: Afatinib is a substrate and inhibitor (Ki=3.4 μM) for P-gp transporter and exposure to afatinib was changed when it was administered with a P-gp inhibitor, ritonavir (AUC increased by 48%) or with a P-gp inducer, rifampicin (AUC decreased by 34%).
Page: -
yes
yes
Tox targets

Tox targets

PubMed

PubMed

TitleDatePubMed
BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.
2008 Aug 7
A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours.
2008 Jan 15
Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification.
2010 Jul 8
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
2010 Nov 24
Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors.
2010 Sep 1
Irreversible EGFR inhibitor EKB-569 targets low-LET γ-radiation-triggered rel orchestration and potentiates cell death in squamous cell carcinoma.
2011
Afatinib (BIBW 2992) development in non-small-cell lung cancer.
2011 Jul
Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors.
2011 Mar 10
Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities.
2011 May
Comprehensive analysis of kinase inhibitor selectivity.
2011 Oct 30
Patents

Sample Use Guides

The recommended dose is 40 mg orally once daily.
Route of Administration: Oral
In cellular in vitro assays, afatinib was able to inhibit phosphorylation and/or proliferation of multiple cell lines representing models of overexpression of wild type EGFR, constitutively active HER2, and EGFR exon 19 deletion mutations, including an exon 19/T790M double mutant. Concentrations of afatinib required for activity in these models ranged from approximately 10 to 100 nM; effects on exon 19/T790M double mutants typically occurred at the high end of this range.
Substance Class Chemical
Created
by admin
on Fri Jun 25 21:32:20 UTC 2021
Edited
by admin
on Fri Jun 25 21:32:20 UTC 2021
Record UNII
41UD74L59M
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
AFATINIB
DASH   INN   MART.   MI   USAN   VANDF   WHO-DD  
INN   USAN  
Official Name English
AFATINIB [WHO-DD]
Common Name English
AFATINIB [MI]
Common Name English
TOVOK
Brand Name English
AFATINIB [USAN]
Common Name English
BIBW 2992
Common Name English
AFATINIB [VANDF]
Common Name English
(2E)-N-(4-(3-CHLORO-4-FLUOROANILINO)-7-(((3S)-OXOLAN-3-YL)OXY)QUINOXAZOLIN-6-YL)-4-(DIMETHYLAMINO)BUT-2-ENAMIDE
Common Name English
TOMTOVOK
Brand Name English
BIBW2992
Code English
AFATINIB [INN]
Common Name English
BIBW-2992
Code English
AFATINIB [MART.]
Common Name English
NSC-750691
Code English
2-BUTENAMIDE, N-(4-((3-CHLORO-4-FLUOROPHENYL)AMINO)-7-(((3S)-TETRAHYDRO-3-FURANYL)OXY)- 6-QUINAZOLINYL)-4-(DIMETHYLAMINO)-, (2E)-
Common Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 690419
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
NDF-RT N0000175605
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
WHO-VATC QL01XE13
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
WHO-ATC L01XE13
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
FDA ORPHAN DRUG 484115
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
NCI_THESAURUS C2167
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
EU-Orphan Drug EU/3/18/2110
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
EMA ASSESSMENT REPORTS GIOTRIF(AUTHORIZED: CARCINOMA, NON-SMALL-CELL LUNG)
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
FDA ORPHAN DRUG 375712
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
FDA ORPHAN DRUG 433414
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
FDA ORPHAN DRUG 781420
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
NCI_THESAURUS C129825
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
Code System Code Type Description
CAS
439081-18-2
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
NON-SPECIFIC STEREOCHEMISTRY
WIKIPEDIA
AFATINIB
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY
PUBCHEM
10184653
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY
DRUG BANK
DB08916
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY
NCI_THESAURUS
C66940
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY
FDA UNII
41UD74L59M
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY
ChEMBL
CHEMBL1173655
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY
MERCK INDEX
M1439
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY Merck Index
CAS
850140-72-6
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY
RXCUI
1430438
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY RxNorm
INN
9230
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY
EVMPD
SUB32268
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY
DRUG CENTRAL
4318
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY
IUPHAR
5667
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY
LACTMED
Afatinib
Created by admin on Fri Jun 25 21:32:20 UTC 2021 , Edited by admin on Fri Jun 25 21:32:20 UTC 2021
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
IRREVERSIBLE INHIBITOR
TARGET -> INHIBITOR
IRREVERSIBLE INHIBITOR
BINDER->LIGAND
BINDING
TARGET -> INHIBITOR
IRREVERSIBLE INHIBITOR
TARGET -> INHIBITOR
a case of successful treatment of a patient aged >80?years with lung adenocarcinoma positive for the uncommon EGFR L861Q mutation with low?dose afatinib. An 83?year?old woman presented with cough and dyspnea. A chest computed tomography (CT) scan revealed tumors in the left upper lobe, left pleural effusion, and multiple lung metastases in both lungs. The patient was diagnosed with lung adenocarcinoma with an EGFR L861Q mutation based on cytological findings. The patient received 30?mg/day of afatinib and experienced no severe adverse events.
SALT/SOLVATE -> PARENT
Related Record Type Details
METABOLITE -> PARENT
minor metabolite
MINOR
URINE
METABOLITE -> PARENT
METABOLITE LESS ACTIVE -> PARENT
METABOLITE -> PARENT
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Biological Half-life PHARMACOKINETIC
Cmax PHARMACOKINETIC
Volume of Distribution PHARMACOKINETIC