Details of the Drug

General Information of Drug (ID: DMTKD7Q)

Drug Name

BIBW 2992

Synonyms

Afatinib; Tomtovok; Tovok; BIBW-2992; Tovok (TN); Tovok, BIBW2992; (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-6-yl}-4-(dimethylamino)but-2-enamide; EGFR inhibitor 2nd gens

Indication

Disease Entry	ICD 11	Status	REF
Non-small-cell lung cancer	2C25.Y	Approved	[1]
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Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

485.9

Logarithm of the Partition Coefficient (xlogp)

3.6

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

Absorption Tmax: The time to maximum plasma concentration (Tmax) is 2-5 h [2]
BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [3]
Clearance: The total body clearance of drug is 1530 mL/min [4]
Elimination: Following administration of an oral solution of 15 mg afatinib, 85.4% of the dose was recovered in the feces and 4.3% in urine [2]
Half-life: The concentration or amount of drug in body reduced by one-half in 37 hours [2]
Metabolism: The drug is metabolized via the enzyme-catalyzed metabolic reactions [2]
Vd: The volume of distribution (Vd) of drug is 4500 L [4]

Chemical Identifiers

Formula: C24H25ClFN5O3
IUPAC Name: (E)-N-[4-(3-chloro-4-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide
Canonical SMILES: CN(C)C/C=C/C(=O)NC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=C(C=C3)F)Cl)O[C@H]4CCOC4
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
InChIKey: ULXXDDBFHOBEHA-CWDCEQMOSA-N

Cross-matching ID

PubChem CID: 10184653
ChEBI ID: CHEBI:61390
CAS Number: 850140-72-6
DrugBank ID: DB08916
TTD ID: D05UFG
VARIDT ID: DR00354

Combinatorial Drugs (CBD)

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Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[5]
Erbb2 tyrosine kinase receptor (HER2)	TT6EO5L	ERBB2_HUMAN	Inhibitor	[5]

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Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[6]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]

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Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Calmodulin-1 (CALM2)	OTNYA92F	CALM1_HUMAN	Drug Response	[7]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Gene/Protein Processing	[8]
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Gene/Protein Processing	[9]
POU domain, class 5, transcription factor 1 (POU5F1)	OTDHHN7O	PO5F1_HUMAN	Gene/Protein Processing	[10]
Protein SET (SET)	OTGYYQJO	SET_HUMAN	Protein Interaction/Cellular Processes	[11]
Ras GTPase-activating-like protein IQGAP1 (IQGAP1)	OTZRWTGA	IQGA1_HUMAN	Post-Translational Modifications	[12]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Molecular Expression Atlas of This Drug

The Studied Disease

Non-small-cell lung cancer

ICD Disease Classification

2C25.Y

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Epidermal growth factor receptor (EGFR)	DTT	EGFR	5.84E-05	0.32	0.55
P-glycoprotein 1 (ABCB1)	DTP	P-GP	1.42E-02	-2.10E-01	-5.11E-01
Breast cancer resistance protein (ABCG2)	DTP	BCRP	1.07E-06	-3.94E-01	-6.94E-01

Molecular Expression Atlas (MEA)

MEA Detail

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Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Same Disease as BIBW 2992

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Disease	REF
PF-06463922	DMKM7EW	Moderate	Accelerated clearance of BIBW 2992 due to the transporter induction by PF-06463922.	Lung cancer [2C25]	[13]
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Coadministration of a Drug Treating the Disease Different from BIBW 2992 (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Remdesivir	DMBFZ6L	Moderate	Increased risk of hepatotoxicity by the combination of BIBW 2992 and Remdesivir.	1D6YCoronavirus Disease 2019 [1D6YCoronavirus Disease 2019]	[14]
Arn-509	DMT81LZ	Moderate	Accelerated clearance of BIBW 2992 due to the transporter induction by Arn-509.	Acute myeloid leukaemia [2A60]	[13]
Ag-221	DMS0ZBI	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Ag-221.	BCR-ABL1-negative chronic myeloid leukaemia [2A41]	[14]
Erdafitinib	DMI782S	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Erdafitinib.	Bladder cancer [2C94]	[15]
Pexidartinib	DMS2J0Z	Major	Increased risk of hepatotoxicity by the combination of BIBW 2992 and Pexidartinib.	Bone/articular cartilage neoplasm [2F7B]	[16]
Talazoparib	DM1KS78	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Talazoparib.	Breast cancer [2C60-2C6Y]	[17]
Cannabidiol	DM0659E	Moderate	Increased risk of hepatotoxicity by the combination of BIBW 2992 and Cannabidiol.	Epileptic encephalopathy [8A62]	[18]
Ripretinib	DM958QB	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Ripretinib.	Gastrointestinal stromal tumour [2B5B]	[14]
Fostemsavir	DM50ILT	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Fostemsavir.	Human immunodeficiency virus disease [1C60-1C62]	[19]
Calaspargase pegol	DMQZBXI	Moderate	Increased risk of hepatotoxicity by the combination of BIBW 2992 and Calaspargase pegol.	Malignant haematopoietic neoplasm [2B33]	[20]
Idelalisib	DM602WT	Moderate	Increased risk of hepatotoxicity by the combination of BIBW 2992 and Idelalisib.	Mature B-cell leukaemia [2A82]	[21]
Ibrutinib	DMHZCPO	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Ibrutinib.	Mature B-cell lymphoma [2A85]	[18]
Arry-162	DM1P6FR	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Arry-162.	Melanoma [2C30]	[14]
Ubrogepant	DM749I3	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Ubrogepant.	Migraine [8A80]	[22]
Rimegepant	DMHOAUG	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Rimegepant.	Migraine [8A80]	[23]
Lasmiditan	DMXLVDT	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Lasmiditan.	Migraine [8A80]	[24]
Rucaparib	DM9PVX8	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Rucaparib.	Ovarian cancer [2C73]	[25]
Darolutamide	DMV7YFT	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Darolutamide.	Prostate cancer [2C82]	[26]
Tedizolid	DMG2SKR	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Tedizolid.	Skin and skin-structure infection [1F28-1G0Z]	[18]
Pitolisant	DM8RFNJ	Moderate	Increased metabolism of BIBW 2992 caused by Pitolisant mediated induction of UGT.	Somnolence [MG42]	[18]
Fostamatinib	DM6AUHV	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Fostamatinib.	Thrombocytopenia [3B64]	[27]
Lusutrombopag	DMH6IKO	Moderate	Decreased clearance of BIBW 2992 due to the transporter inhibition by Lusutrombopag.	Thrombocytopenia [3B64]	[25]
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⏷ Show the Full List of 22 DDI Information of This Drug

References

1	URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5667).
2	Electronic Medicines Compendium: Giotrif 30 mg film-coated tablets Monograph
3	BDDCS predictions, self-correcting aspects of BDDCS assignments, BDDCS assignment corrections, and classification for more than 175 additional drugs
4	Stopfer P, Marzin K, Narjes H, Gansser D, Shahidi M, Uttereuther-Fischer M, Ebner T: Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers. Cancer Chemother Pharmacol. 2012 Apr;69(4):1051-61. doi: 10.1007/s00280-011-1803-9. Epub 2011 Dec 27.
5	Boehringer Ingelheim. Product Development Pipeline. June 2 2009.
6	Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-gp/ABCB1) transport afatinib and restrict its oral availability and brain accumulation. Pharmacol Res. 2017 Jun;120:43-50.
7	Knockdown of CALM2 increases the sensitivity to afatinib in HER2-amplified gastric cancer cells by regulating the Akt/FoxO3a/Puma axis. Toxicol In Vitro. 2023 Mar;87:105531. doi: 10.1016/j.tiv.2022.105531. Epub 2022 Nov 29.
8	Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors. J Med Chem. 2011 Mar 10;54(5):1347-55. doi: 10.1021/jm101396q. Epub 2011 Feb 15.
9	Irreversible EGFR inhibitor EKB-569 targets low-LET -radiation-triggered rel orchestration and potentiates cell death in squamous cell carcinoma. PLoS One. 2011;6(12):e29705. doi: 10.1371/journal.pone.0029705. Epub 2011 Dec 29.
10	YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells. PLoS One. 2017 Aug 7;12(8):e0182149. doi: 10.1371/journal.pone.0182149. eCollection 2017.
11	Oncoprotein SET dynamically regulates cellular stress response through nucleocytoplasmic transport in breast cancer. Cell Biol Toxicol. 2023 Aug;39(4):1795-1814. doi: 10.1007/s10565-022-09784-4. Epub 2022 Dec 19.
12	Tyrosine phosphorylation of the scaffold protein IQGAP1 in the MET pathway alters function. J Biol Chem. 2020 Dec 25;295(52):18105-18121. doi: 10.1074/jbc.RA120.015891. Epub 2020 Oct 21.
13	Product Information. Gilotrif (afatinib). Boehringer Ingelheim, Ridgefield, CT.
14	Cerner Multum, Inc. "Australian Product Information.".
15	Product Information. Balversa (erdafitinib). Janssen Products, LP, Horsham, PA.
16	Product Information. Turalio (pexidartinib). Daiichi Sankyo, Inc., Parsippany, NJ.
17	Product Information. Talzenna (talazoparib). Pfizer U.S. Pharmaceuticals Group, New York, NY.
18	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
19	Product Information. Rukobia (fostemsavir). ViiV Healthcare, Research Triangle Park, NC.
20	Al-Nawakil C, Willems L, Mauprivez C, et.al "Successful treatment of l-asparaginase-induced severe acute hepatotoxicity using mitochondrial cofactors." Leuk Lymphoma 55 (2014): 1670-4. [PMID: 24090500]
21	Product Information. Zydelig (idelalisib). Gilead Sciences, Foster City, CA.
22	Product Information. Ubrelvy (ubrogepant). Allergan Inc, Irvine, CA.
23	Product Information. Nurtec ODT (rimegepant). Biohaven Pharmaceuticals, New Haven, CT.
24	Product Information. Reyvow (lasmiditan). Lilly, Eli and Company, Indianapolis, IN.
25	EMA. European Medicines Agency. European Union "EMA - List of medicines under additional monitoring.".
26	Product Information. Nubeqa (darolutamide). Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ.
27	Product Information. Tavalisse (fostamatinib). Rigel Pharmaceuticals, South San Francisco, CA.