Afatinib

Identification

Name

Afatinib

Accession Number

DB08916

Description

Afatinib is a 4-anilinoquinazoline tyrosine kinase inhibitor in the form of a dimaleate salt available as Boehringer Ingelheim's brand name Gilotrif ^Label. For oral use, afatinib tablets are a first-line (initial) treatment for patients with metastatic non-small cell lung cancer (NSCLC) with common epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test ⁴. Gilotrif (afatinib) is the first FDA-approved oncology product from Boehringer Ingelheim ⁴.

Type

Small Molecule

Groups

Approved

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Afatinib (DB08916)

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Weight

Average: 485.938
Monoisotopic: 485.162995603

Chemical Formula

C₂₄H₂₅ClFN₅O₃

Synonyms

• Afatinib
• Afatinibum

External IDs

• BIBW 2992
• BIBW-2992
• BIBW2992

Pharmacology

Indication

Afatinib is a kinase inhibitor indicated as monotherapy ³ for the first-line ^Label treatment of (a) Epidermal Growth Factor Receptor (EGFR) TKI (tyrosine kinase inhibitor)-naive adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have non-resistant EGFR mutations as detected by an FDA-approved test ^Label, and (b) adult patients with locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy ^Label,3.

Recently, as of January 2018, the US FDA approved a supplemental New Drug Application for Boehringer Ingelheim's Gilotrif (afatinib) for the first line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test ⁴. The new label includes data on three additional EGFR mutations: L861Q, G719X and S768I ⁴.

Associated Conditions

• Metastatic Non-Small Cell Lung Cancer
• Refractory, metastatic squamous cell Non-small cell lung cancer

Contraindications & Blackbox Warnings

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Pharmacodynamics

Aberrant ErbB signaling triggered by receptor mutations, and/or amplification, and/or receptor ligand overexpression contributes to the malignant phenotype ³. Mutation in EGFR defines a distinct molecular subtype of lung cancer ³.

In non-clinical disease models with ErbB pathway deregulation, afatinib as a single agent effectively blocks ErbB receptor signaling resulting in tumor growth inhibition or tumor regression ³. NSCLC tumors with common activating EGFR mutations (Del 19, L858R) and several less common EGFR mutations in exon 18 (G719X) and exon 21 (L861Q) are particularly sensitive to afatinib treatment in non-clinical and clinical settings ³. Limited non-clinical and/or clinical activity was observed in NSCLC tumors with insertion mutations in exon 20 ³.

The acquisition of a secondary T790M mutation is a major mechanism of acquired resistance to afatinib and gene dosage of the T790M-containing allele correlates with the degree of resistance in vitro ³. The T790M mutation is found in approximately 50% of patients' tumors upon disease progression on afatinib, for which T790M targeted EGFR TKIs may be considered as a next line treatment option ³. Other potential mechanisms of resistance to afatinib have been suggested preclinically and MET gene amplification has been observed clinically ³.

At the same time, the effect of multiple doses of afatinib (50 mg once daily) on cardiac electrophysiology and the QTc interval was evaluated in an open-label, single-arm study in patients with relapsed or refractory solid tumors ^Label. Ultimately, no large changes in the mean QTc interval (i.e., >20 ms) were detected in the study ^Label.

Mechanism of action

Afatinib is a potent and selective, irreversible ErbB family blocker ³. Afatinib covalently binds to and irreversibly blocks signaling from all homo and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4 ³.

In particular, afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling ^Label. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC ^Label. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods ^Label. The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions ^Label.

Moreover, afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients ^Label. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2 ^Label.

Target	Actions	Organism
AEpidermal growth factor receptor	inhibitor	Humans
AReceptor tyrosine-protein kinase erbB-2	inhibitor	Humans
AReceptor tyrosine-protein kinase erbB-4	inhibitor	Humans

Absorption

Following oral administration, time to peak plasma concentration (Tmax) is 2 to 5 hours ^Label. Maximum concentration (Cmax) and area under the concentration-time curve from time zero to infinity (AUC0-∞) values increased slightly more than dose proportional in the range of 20 to 50 mg ^Label. The geometric mean relative bioavailability of 20 mg tablets was 92% as compared to an oral solution ^Label.

Additionally, systemic exposure to afatinib is decreased by 50% (Cmax) and 39% (AUC0-∞), when administered with a high-fat meal compared to administration in the fasted state ³. Based on population pharmacokinetic data derived from clinical trials in various tumor types, an average decrease of 26% in AUCss was observed when food was consumed within 3 hours before or 1 hour after taking afatinib ³.

Volume of distribution

The volume of distribution of afatinib recorded in healthy male volunteers is documented as 4500 L ². Such a high volume of distribution in plasma suggests a potentially high tissue distribution ².

Protein binding

In vitro binding of afatinib to human plasma proteins is approximately 95% ³. Afatinib binds to proteins both non-covalently (traditional protein binding) and covalently ³.

Metabolism

Enzyme-catalyzed metabolic reactions play a negligible role for afatinib in vivo ³. Covalent adducts to proteins were the major circulating metabolites of afatinib ³.

Route of elimination

In humans, excretion of afatinib is primarily via the feces ³. 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 ³. The parent compound afatinib accounted for 88% of the recovered dose ³.

Half-life

Afatinib is eliminated with an effective half-life of approximately 37 hours ³. Thus, steady-state plasma concentrations of afatinib were achieved within 8 days of multiple dosing of afatinib resulting in an accumulation of 2.77-fold (AUC0-∞) and 2.11-fold (Cmax) ³. In patients treated with afatinib for more than 6 months, a terminal half-life of 344 h was estimated ³.

Clearance

The apparent total body clearance of afatinib as recorded in healthy male volunteers is documented as being a high geometric mean of 1530 mL/min ².

Adverse Effects

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Toxicity

Most common adverse reactions (≥20%) are diarrhea, rash/dermatitis, acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus ^Label.

Conversely, overdose in 2 healthy adolescents involving the ingestion of 360 mg each of afatinib (as part of a mixed drug ingestion) was associated with adverse events of nausea, vomiting, asthenia, dizziness, headache, abdominal pain and elevated amylase (< 1.5 times ULN) ³. Both individuals recovered from these adverse events ³.

Affected organisms

• Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Interacting Gene/Enzyme	Allele name	Genotype(s)	Defining Change(s)	Type(s)	Description	Details
Epidermal growth factor receptor	L861Q	(A;A) / (A;T) / (G;G) / (G;T)	T > A or G	Effect Directly Studied	The presence of this polymorphism in EGFR is associated with a higher response rate to afatinib.	Details
Epidermal growth factor receptor	L858R	(G;G) / (G;T)	T > G	Effect Directly Studied	The presence of this polymorphism in EGFR is associated with a higher response rate to afatinib.	Details
Epidermal growth factor receptor	G719A/C	(T;T) / (G;T) / (A;A) / (A;G) / (C;C) / (C;G)	G > A or C or T	Effect Directly Studied	The presence of this polymorphism in EGFR is associated with a higher response rate to afatinib.	Details

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abaloparatide	The therapeutic efficacy of Abaloparatide can be decreased when used in combination with Afatinib.
Abemaciclib	Afatinib may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Acetaminophen	The serum concentration of Acetaminophen can be increased when it is combined with Afatinib.
Alectinib	Alectinib may decrease the excretion rate of Afatinib which could result in a higher serum level.
Allopurinol	Afatinib may decrease the excretion rate of Allopurinol which could result in a higher serum level.
Alpelisib	The serum concentration of Alpelisib can be increased when it is combined with Afatinib.
Ambrisentan	The serum concentration of Ambrisentan can be increased when it is combined with Afatinib.
Amiodarone	The serum concentration of Afatinib can be increased when it is combined with Amiodarone.
Apalutamide	The serum concentration of Afatinib can be decreased when it is combined with Apalutamide.
Apixaban	The serum concentration of Apixaban can be increased when it is combined with Afatinib.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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Severity
Severity
A severity rating for each drug interaction, from minor to major.
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Evidence Level
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
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Action
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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Food Interactions

• Take separate from meals. Take at least one hour before or two hours after a meal.

Products

Product Ingredients

Ingredient	UNII	CAS	InChI Key
Afatinib dimaleate	V1T5K7RZ0B	850140-73-7	USNRYVNRPYXCSP-JUGPPOIOSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Unlock Additional Data
Gilotrif	Tablet, film coated	40 mg/1	Oral	Boehringer Ingelheim Pharmaceuticals, Inc.	2013-07-12	Not applicable
Gilotrif	Tablet, film coated	30 mg/1	Oral	Boehringer Ingelheim Pharmaceuticals, Inc.	2013-07-12	Not applicable
Gilotrif	Tablet, film coated	20 mg/1	Oral	Boehringer Ingelheim Pharmaceuticals, Inc.	2013-07-12	Not applicable
Giotrif	Tablet		Oral	Boehringer Ingelheim (Canada) Ltd Ltee	2014-01-17	Not applicable
Giotrif	Tablet		Oral	Boehringer Ingelheim (Canada) Ltd Ltee	2014-01-17	Not applicable
Giotrif	Tablet		Oral	Boehringer Ingelheim (Canada) Ltd Ltee	2014-01-17	Not applicable

Additional Data Available

Application Number
Application Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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Categories

ATC Codes

L01XE13 — Afatinib

• L01XE — Protein kinase inhibitors
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Amides
• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• BCRP/ABCG2 Inhibitors
• BCRP/ABCG2 Substrates
• Enzyme Inhibitors
• Heterocyclic Compounds, Fused-Ring
• Kinase Inhibitor
• P-glycoprotein inhibitors
• P-glycoprotein substrates
• Protein Kinase Inhibitors
• Quinazolines
• Tyrosine Kinase Inhibitors

Chemical TaxonomyProvided by Classyfire

Description

This 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.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Diazanaphthalenes

Sub Class

Benzodiazines

Direct Parent

Quinazolinamines

Alternative Parents

N-arylamides / Aniline and substituted anilines / Chlorobenzenes / Fluorobenzenes / Aminopyrimidines and derivatives / Alkyl aryl ethers / Imidolactams / Aryl chlorides / Aryl fluorides / Tetrahydrofurans / Heteroaromatic compounds / Amino acids and derivatives / Trialkylamines / Secondary carboxylic acid amides / Azacyclic compounds / Dialkyl ethers / Oxacyclic compounds / Secondary amines / Carbonyl compounds / Hydrocarbon derivatives / Organic oxides / Organochlorides / Organofluorides / Organopnictogen compounds

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Substituents

Alkyl aryl ether / Amine / Amino acid or derivatives / Aminopyrimidine / Aniline or substituted anilines / Aromatic heteropolycyclic compound / Aryl chloride / Aryl fluoride / Aryl halide / Azacycle / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Chlorobenzene / Dialkyl ether / Ether / Fluorobenzene / Halobenzene / Heteroaromatic compound / Hydrocarbon derivative / Imidolactam / Monocyclic benzene moiety / N-arylamide / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organochloride / Organofluoride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Oxacycle / Pyrimidine / Quinazolinamine / Secondary amine / Secondary carboxylic acid amide / Tertiary aliphatic amine / Tertiary amine / Tetrahydrofuran

show 31 more

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

organofluorine compound, tertiary amino compound, aromatic ether, enamide, furans, monochlorobenzenes, quinazolines (CHEBI:61390)

Chemical Identifiers

UNII

41UD74L59M

CAS number

850140-72-6

InChI Key

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

References

General References

1. Wind S, Schnell D, Ebner T, Freiwald M, Stopfer P: Clinical Pharmacokinetics and Pharmacodynamics of Afatinib. Clin Pharmacokinet. 2017 Mar;56(3):235-250. doi: 10.1007/s40262-016-0440-1. [PubMed:27470518]
2. 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. [PubMed:22200729]
3. Electronic Medicines Compendium: Giotrif 30 mg film-coated tablets Monograph [Link]
4. Boehringer Ingelheim: FDA approves new indication for Gilotrif® in EGFR mutation-positive NSCLC [Link]

External Links

KEGG Drug

D09724

PubChem Compound

10184653

PubChem Substance

175427153

ChemSpider

8360155

BindingDB

50322823

RxNav

1430438

ChEBI

61390

ChEMBL

CHEMBL1173655

ZINC

ZINC000003976838

PharmGKB

PA165981154

PDBe Ligand

0WM

Drugs.com

Drugs.com Drug Page

Wikipedia

Afatinib

AHFS Codes

• 10:00.00 — Antineoplastic Agents

PDB Entries

4g5j

FDA label

Download (427 KB)

MSDS

Download (26.7 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	ErbB Receptors / Non-Small Cell Lung Carcinoma (NSCLC)	1
4	Completed	Treatment	Non-Small Cell Lung Carcinoma (NSCLC)	1
4	Recruiting	Treatment	Lung Squamous Cell Carcinoma	1
4	Recruiting	Treatment	Non-squamous NSCLC	1
4	Terminated	Treatment	ErbB Receptors / Non-Small Cell Lung Carcinoma (NSCLC)	1
3	Active Not Recruiting	Treatment	Head and Neck Squamous Cell Carcinoma (HNSCC)	1
3	Active Not Recruiting	Treatment	Neoplasms, Head and Neck	1
3	Active Not Recruiting	Treatment	Non-Small Cell Lung Carcinoma (NSCLC)	1
3	Completed	Treatment	Adenocarcinomas / Non-Small Cell Lung Carcinoma (NSCLC)	2
3	Completed	Treatment	Neoplasms, Breast	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	20 mg/1
Tablet, film coated	Oral	30 mg/1
Tablet, film coated	Oral	40 mg/1
Tablet	Oral
Tablet, film coated	Oral
Tablet, film coated	Oral	20 MG
Tablet, film coated	Oral	30 MG
Tablet, film coated	Oral	40 MG
Tablet, film coated	Oral	50 MG
Tablet, coated		20 mg
Tablet
Tablet, coated		30 mg
Tablet, coated		40 mg
Tablet, coated	Oral	20 mg
Tablet, coated	Oral	30 mg
Tablet, coated	Oral	40 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
Unlock Additional Data
US6251912	No	2001-06-26	2018-07-29
US8426586	No	2013-04-23	2029-10-10
USRE43431	No	2012-05-29	2022-01-22
US8545884	No	2013-10-01	2029-12-19
US9539258	No	2017-01-10	2026-11-09
US10004743	No	2018-06-26	2030-07-05

Additional Data Available

Filed On
Filed On
The date on which a patent was filed with the relevant government.
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Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0128 mg/mL	ALOGPS
logP	3.77	ALOGPS
logP	3.76	ChemAxon
logS	-4.6	ALOGPS
pKa (Strongest Acidic)	12.49	ChemAxon
pKa (Strongest Basic)	8.81	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	7	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	88.61 Å2	ChemAxon
Rotatable Bond Count	8	ChemAxon
Refractivity	131.38 m3·mol-1	ChemAxon
Polarizability	50.07 Å3	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	1.0
Blood Brain Barrier	+	0.8717
Caco-2 permeable	-	0.5342
P-glycoprotein substrate	Substrate	0.744
P-glycoprotein inhibitor I	Inhibitor	0.6776
P-glycoprotein inhibitor II	Inhibitor	0.9036
Renal organic cation transporter	Non-inhibitor	0.7154
CYP450 2C9 substrate	Non-substrate	0.7919
CYP450 2D6 substrate	Non-substrate	0.8034
CYP450 3A4 substrate	Substrate	0.7504
CYP450 1A2 substrate	Non-inhibitor	0.5236
CYP450 2C9 inhibitor	Non-inhibitor	0.7294
CYP450 2D6 inhibitor	Non-inhibitor	0.7625
CYP450 2C19 inhibitor	Non-inhibitor	0.5877
CYP450 3A4 inhibitor	Non-inhibitor	0.6486
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.7096
Ames test	Non AMES toxic	0.5695
Carcinogenicity	Non-carcinogens	0.8692
Biodegradation	Not ready biodegradable	1.0
Rat acute toxicity	2.5643 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.8956
hERG inhibition (predictor II)	Inhibitor	0.7228

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

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Drug created on July 17, 2013 15:59 / Updated on October 23, 2020 21:53