AFATINIB DIMALEATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C24H25ClFN5O3.2C4H4O4
Molecular Weight	718.083
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	3
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.CN(C)C\C=C\C(=O)NC1=CC2=C(C=C1O[C@H]3CCOC3)N=CN=C2NC4=CC(Cl)=C(F)C=C4

InChI

InChIKey=USNRYVNRPYXCSP-JUGPPOIOSA-N

InChI=1S/C24H25ClFN5O3.2C4H4O4/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;2*5-3(6)1-2-4(7)8/h3-6,10-12,14,16H,7-9,13H2,1-2H3,(H,30,32)(H,27,28,29);2*1-2H,(H,5,6)(H,7,8)/b4-3+;2*2-1-/t16-;;/m0../s1

HIDE SMILES / InChI

Molecular Formula	C4H4O4
Molecular Weight	116.0722
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
Optical Activity	NONE

Molecular Formula	C24H25ClFN5O3
Molecular Weight	485.938
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	1
Optical Activity	UNSPECIFIED

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/201292s009lbl.pdf
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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Epidermal growth factor receptor 46 Target ID: P00533\|\|\|Q9GZX1 Gene ID: 1956.0 Gene Symbol: EGFR Target Organism: Homo sapiens (Human) Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/201292s009lbl.pdf	Antagonist 2778	0.5 nM [IC50]
Receptor tyrosine-protein kinase erbB-2 5 Target ID: P04626 Gene ID: 2064.0 Gene Symbol: ERBB2 Target Organism: Homo sapiens (Human) Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/201292s009lbl.pdf	Antagonist 2778	14.0 nM [IC50]
Receptor tyrosine-protein kinase erbB-4 4 Target ID: Q15303 Gene ID: 2066.0 Gene Symbol: ERBB4 Target Organism: Homo sapiens (Human) Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/201292s009lbl.pdf	Antagonist 2778	0.7 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Non-small cell lung cancer 206 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/201292s009lbl.pdf	Primary		Approved 8429	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

C_max

Value	Dose	Analyte	Population
42.7 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29337963	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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24906422	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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24906422	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

Value	Dose	Analyte	Population
683 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29337963	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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24906422	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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24906422	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
74.9 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24906422	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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24906422	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

F_unbound

Value	Dose	Co-administered	Analyte	Population
5% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf			AFATINIB plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
50 mg 1 times / day multiple, oral Dose: 50 mg, 1 times / day Route: oral Route: multiple Dose: 50 mg, 1 times / day Sources: https://www.ema.europa.eu/en/documents/assessment-report/giotrif-epar-public-assessment-report_en.pdf https://pubmed.ncbi.nlm.nih.gov/22452896/	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: https://www.ema.europa.eu/en/documents/assessment-report/giotrif-epar-public-assessment-report_en.pdf https://pubmed.ncbi.nlm.nih.gov/22452896/	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: https://www.ema.europa.eu/en/documents/assessment-report/giotrif-epar-public-assessment-report_en.pdf https://pubmed.ncbi.nlm.nih.gov/22452896/
50 mg 1 times / day multiple, oral Dose: 50 mg, 1 times / day Route: oral Route: multiple Dose: 50 mg, 1 times / day Sources: https://www.ema.europa.eu/en/documents/assessment-report/giotrif-epar-public-assessment-report_en.pdf https://pubmed.ncbi.nlm.nih.gov/22452896/	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: https://www.ema.europa.eu/en/documents/assessment-report/giotrif-epar-public-assessment-report_en.pdf https://pubmed.ncbi.nlm.nih.gov/22452896/	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: https://www.ema.europa.eu/en/documents/assessment-report/giotrif-epar-public-assessment-report_en.pdf https://pubmed.ncbi.nlm.nih.gov/22452896/
360 mg 1 times / day single, oral Dose: 360 mg, 1 times / day Route: oral Route: single Dose: 360 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf	healthy, adolescents n = 2 Health Status: healthy Age Group: adolescents Population Size: 2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf	Other AEs: Nausea, Vomiting... Other AEs: Nausea Vomiting Asthenia Dizziness Headache Abdominal pain Amylase increased Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf
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: https://pubmed.ncbi.nlm.nih.gov/18026190/	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: https://pubmed.ncbi.nlm.nih.gov/18026190/	DLT: Skin rash, Diarrhoea... Dose limiting toxicities: Skin rash (grade 3, 50%) Diarrhoea (grade 3, 50%) Sources: https://pubmed.ncbi.nlm.nih.gov/18026190/
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: https://pubmed.ncbi.nlm.nih.gov/18026190/	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: https://pubmed.ncbi.nlm.nih.gov/18026190/	DLT: Fatigue, ALT increased... Dose limiting toxicities: Fatigue (grade 3, 5.6%) ALT increased (grade 3, 5.6%) Sources: https://pubmed.ncbi.nlm.nih.gov/18026190/
70 mg 1 times / day multiple, oral Dose: 70 mg, 1 times / day Route: oral Route: multiple Dose: 70 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18026190/	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: https://pubmed.ncbi.nlm.nih.gov/18026190/	DLT: Diarrhoea... Dose limiting toxicities: Diarrhoea (grade 3, 11.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/18026190/
85 mg 1 times / day multiple, oral Dose: 85 mg, 1 times / day Route: oral Route: multiple Dose: 85 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18026190/	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: https://pubmed.ncbi.nlm.nih.gov/18026190/	DLT: Diarrhoea, Diarrhoea... Dose limiting toxicities: Diarrhoea (grade 3, 16.7%) Diarrhoea (grade 2, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/18026190/
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/23816960/	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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/23816960/	Disc. AE: Diarrhea, Paronychia... AEs leading to discontinuation/dose reduction: Diarrhea (1.3%) Paronychia (0.9%) Interstitial lung disease (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/23816960/
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/23816960/	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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/23816960/	Other AEs: Diarrhea, Stomatitis... Other AEs: Diarrhea (grade 3, 15%) Stomatitis (grade 3, 8%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/23816960/
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000MedR.pdf https://www.boehringer-ingelheim.ca/sites/ca/files/documents/giotrifpmen.pdf	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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000MedR.pdf https://www.boehringer-ingelheim.ca/sites/ca/files/documents/giotrifpmen.pdf	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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000MedR.pdf https://www.boehringer-ingelheim.ca/sites/ca/files/documents/giotrifpmen.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000MedR.pdf 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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000MedR.pdf 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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000MedR.pdf Page: 201292Orig1s000MedR.pdf - p.66

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	inhibitor 1767 inducer 389	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 BCRP 699 CYP1A 72 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1478 CYP2E1 882 CYP4A11 21	P-gp 1537 FMO3 67 BCRP 561	CYP1A2 701 CYP2B6 547 CYP2C8 168 CYP2C19 293

Drug as perpetrator

Target	Modality	Activity
CYP1A 121	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=41 Page: -	no
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=42 Page: -	no
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=41 Page: -	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=42 Page: -	no
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=41 Page: -	no
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=42 Page: -	no
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=41 Page: -	no
CYP2C8 965	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=42 Page: -	no
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=41 Page: -	no
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=42 Page: -	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=41 Page: -	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=41 Page: -	no
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=41 Page: -	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=42 Page: -	no
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=41 Page: -	no
CYP4A11 25	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=41 Page: -	no
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=44 Page: -	yes [IC50 0.75 uM]
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=15 Page: -	yes [Ki 3.4 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=32 Page: -	minor
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=15 Page: -	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%). Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=15 Page: -
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=44 Page: -	yes
FMO3 67	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000ClinPharmR.pdf#page=32 Page: -	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/201292Orig1s000PharmR.pdf#page=5 Page: -

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:61390	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:61390
ChemicalBook	CB12470923	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB12470923
ChemicalBook	CB62507657	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB62507657
MolPort	MolPort-009-679-394	https://www.molport.com/shop/molecule-link/MolPort-009-679-394
Selleck Chemicals	BIBW2992	http://www.selleckchem.com/products/BIBW2992.html
ZINC	ZINC000003976838	http://zinc15.docking.org/substances/ZINC000003976838

PubMed

Title	Date	PubMed
BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.	2008 Aug 7	18408761
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	18026190
Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification.	2010 Jul 8	20550212
Irreversible EGFR inhibitor EKB-569 targets low-LET γ-radiation-triggered rel orchestration and potentiates cell death in squamous cell carcinoma.	2011	22242139
Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors.	2011 Mar 10	21322567

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose is 40 mg orally once daily.

Route of Administration: Oral

In Vitro Use Guide

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 Dec 15 15:56:21 UTC 2023` Edited by `admin` on `Fri Dec 15 15:56:21 UTC 2023`
Record UNII	V1T5K7RZ0B
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

AFATINIB DIMALEATE

Official Name

English

AFATINIB DIMALEATE [MI]

Common Name

English

BIBW-2992MA2

Code

English

AFATINIB DIMALEATE [USAN]

Common Name

English

BIBW-2992 MA2

Code

English

GILOTRIF

Brand Name

English

2-BUTENAMIDE, N-(4-((3-CHLORO-4-FLUOROPHENYL)AMINO)-7-(((3S)-TETRAHYDRO-3-FURANYL)OXY)-6-QUINAZOLINYL)-4-(DIMETHYLAMINO)-, (2E)-, (2Z)-2-BUTENEDIOATE (1:2)

Common Name

English

BIBW2992 MA2

Code

English

(2E)-N-(4-((3-CHLORO-4-FLUOROPHENYL)AMINO)-7-(((3S)-TETRAHYDROFURAN-3-YL)OXY)QUINAZOLIN- 6-YL)-4-(DIMETHYLAMINO)BUT-2-ENAMIDE BIS(HYDROGEN (2Z)-BUT-2-ENEDIOATE)

Common Name

English

AFATINIB MALEATE

Official Name

English

BIBW-2992-MA2

Code

English

AFATINIB DIMALEATE [VANDF]

Common Name

English

BIBW2992-MA2

Code

English

AFATINIB DIMALEATE [ORANGE BOOK]

Common Name

English

Afatinib dimaleate [WHO-DD]

Common Name

English

GIOTRIF

Brand Name

English

AFATINIB MALEATE [JAN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C129825