Identification

Name
Afatinib
Accession Number
DB08916
Type
Small Molecule
Groups
Approved
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].

Structure
Thumb
Synonyms
  • Afatinibum
External IDs
BIBW 2992 / BIBW-2992 / BIBW2992
Product Ingredients
IngredientUNIICASInChI Key
Afatinib dimaleateV1T5K7RZ0B850140-73-7USNRYVNRPYXCSP-JUGPPOIOSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
GilotrifTablet, film coated20 mg/1OralBoehringer Ingelheim Pharmaceuticals, Inc.2013-07-12Not applicableUs
GilotrifTablet, film coated40 mg/1OralBoehringer Ingelheim Pharmaceuticals, Inc.2013-07-12Not applicableUs
GilotrifTablet, film coated30 mg/1OralBoehringer Ingelheim Pharmaceuticals, Inc.2013-07-12Not applicableUs
GiotrifTablet20 mgOralBoehringer Ingelheim (Canada) Ltd Ltee2014-01-17Not applicableCanada
GiotrifTablet40 mgOralBoehringer Ingelheim (Canada) Ltd Ltee2014-01-17Not applicableCanada
GiotrifTablet30 mgOralBoehringer Ingelheim (Canada) Ltd Ltee2014-01-17Not applicableCanada
Categories
UNII
41UD74L59M
CAS number
850140-72-6
Weight
Average: 485.938
Monoisotopic: 485.162995603
Chemical Formula
C24H25ClFN5O3
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[C@H]2CCOC2)C=C2N=CN=C(NC3=CC(Cl)=C(F)C=C3)C2=C1

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].

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
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].

TargetActionsOrganism
AEpidermal growth factor receptor
inhibitor
Human
AReceptor tyrosine-protein kinase erbB-2
inhibitor
Human
AReceptor tyrosine-protein kinase erbB-4
inhibitor
Human
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].

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/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Epidermal growth factor receptorL861Q(A;A) / (A;T) / (G;G) / (G;T)T > A or GEffect Directly StudiedThe presence of this polymorphism in EGFR is associated with a higher response rate to afatinib.Details
Epidermal growth factor receptorL858R(G;G) / (G;T)T > GEffect Directly StudiedThe presence of this polymorphism in EGFR is associated with a higher response rate to afatinib.Details
Epidermal growth factor receptorG719A/C(T;T) / (G;T) / (A;A) / (A;G) / (C;C) / (C;G)G > A or C or TEffect Directly StudiedThe presence of this polymorphism in EGFR is associated with a higher response rate to afatinib.Details

Interactions

Drug Interactions
DrugInteraction
AbemaciclibThe serum concentration of Afatinib can be increased when it is combined with Abemaciclib.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Afatinib.
AcetaminophenThe serum concentration of Afatinib can be increased when it is combined with Acetaminophen.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Afatinib.
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Afatinib.
Acetylsalicylic acidThe serum concentration of Acetylsalicylic acid can be increased when it is combined with Afatinib.
AlbendazoleThe serum concentration of Afatinib can be increased when it is combined with Albendazole.
AldosteroneThe serum concentration of Afatinib can be decreased when it is combined with Aldosterone.
AlectinibThe serum concentration of Afatinib can be increased when it is combined with Alectinib.
AlitretinoinThe serum concentration of Alitretinoin can be increased when it is combined with Afatinib.
Food Interactions
  • When given with a high-fat meal, Cmax decreases by 50% and AUC by 39% relative to the fasted state.

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
ChEBI
61390
ChEMBL
CHEMBL1173655
PharmGKB
PA165981154
HET
0WM
Drugs.com
Drugs.com Drug Page
Wikipedia
Afatinib
ATC Codes
L01XE13 — 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
PhaseStatusPurposeConditionsCount
1Active Not RecruitingOtherPancreatic Cancer Metastatic1
1Active Not RecruitingTreatmentGlioblastomas1
1Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Lung Cancers1
1Active Not RecruitingTreatmentSquamous Cell Carcinoma of the Head and Neck (SCCHN)1
1CompletedTreatmentHNSCC1
1CompletedTreatmentHead and Neck Carcinoma / Squamous Cell Cancer1
1CompletedTreatmentHealthy Volunteers3
1CompletedTreatmentHealthy Volunteers / Liver Diseases1
1CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)4
1CompletedTreatmentNeoplasms14
1CompletedTreatmentNeoplasms, Breast1
1CompletedTreatmentNeoplasms, Breast / Stomach Neoplasms1
1Not Yet RecruitingTreatmentMetastatic Squamous Cell Carcinoma of the Head or Neck / Platinum- and Cetuximab-Refractory Squamous Cell Carcinoma of the Head or Neck / Recurrent Squamous Cell Carcinoma of the Head or Neck / Squamous Cell Carcinoma (SCC)1
1RecruitingTreatmentAdvanced Malignant Solid Neoplasm / Bile Duct Carcinoma / Recurrent Malignant Solid Neoplasm / Recurrent Pancreatic Carcinoma / Solid Neoplasms / Stage III Pancreatic Cancer / Stage III Pancreatic Cancer AJCC v6 and v7 / Stage IVA Pancreatic Cancer / Stage IVB Pancreatic Cancer1
1RecruitingTreatmentBrain Cancer1
1RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
1RecruitingTreatmentRecurrent Non-Small Cell Lung Carcinoma / Stage IIIA Non-Small Cell Lung Cancer / Stage IIIb Non-small Cell Lung Cancer / Stage IV Non-Small Cell Lung Cancer1
1TerminatedTreatmentMetastatic Disease1
1WithdrawnTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
1, 2Not Yet RecruitingTreatmentEGFR Mutation Positive Non Small Cell Lung Cancer1
1, 2RecruitingOtherAdvanced Breast Cancer / Advanced Lung Cancer / Brain Cancer / Cancer, Breast / Lung Cancers1
1, 2RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Neoplasms, Colorectal / Neoplasms, Gastrointestinal / Neoplasms, Pancreatic1
1, 2RecruitingTreatmentNeuroectodermal Tumors / Rhabdomyosarcomas1
1, 2TerminatedTreatmentSquamous Cell Carcinoma of the Head and Neck (SCCHN)1
1, 2Unknown StatusTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2Active Not RecruitingTreatmentEGFR Gene Mutations / Neoplasms, Lung1
2Active Not RecruitingTreatmentEGFR / Her-2 / Lung Cancer Non-Small Cell Cancer (NSCLC)1
2Active Not RecruitingTreatmentFocus of Study Instead1
2Active Not RecruitingTreatmentHead and Neck Squamous Cell Carcinoma (HNSCC) / Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma / Salivary Gland Squamous Cell Carcinoma / Stage III Salivary Gland Cancer / Stage III Squamous Cell Carcinoma of the Hypopharynx / Stage III Squamous Cell Carcinoma of the Larynx / Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity / Stage III Squamous Cell Carcinoma of the Oropharynx / Stage III Verrucous Carcinoma of the Larynx / Stage III Verrucous Carcinoma of the Oral Cavity / Stage IV Squamous Cell Carcinoma of the Hypopharynx / Stage IV Squamous Cell Carcinoma of the Larynx / Stage IVA Salivary Gland Cancer / Stage IVA Squamous Cell Carcinoma of the Larynx / Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity / Stage IVA Squamous Cell Carcinoma of the Oropharynx / Stage IVA Verrucous Carcinoma of the Larynx / Stage IVA Verrucous Carcinoma of the Oral Cavity / Stage IVB Salivary Gland Cancer / Stage IVB Squamous Cell Carcinoma of the Larynx / Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity / Stage IVB Squamous Cell Carcinoma of the Oropharynx / Stage IVB Verrucous Carcinoma of the Larynx / Stage IVB Verrucous Carcinoma of the Oral Cavity / Stage IVC Salivary Gland Cancer / Stage IVC Squamous Cell Carcinoma of the Larynx / Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity / Stage IVC Squamous Cell Carcinoma of the Oropharynx / Stage IVC Verrucous Carcinoma of the Larynx / Stage IVC Verrucous Carcinoma of the Oral Cavity / Tongue Cancer1
2Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)3
2Active Not RecruitingTreatmentMetastatic Cancers1
2Active Not RecruitingTreatmentNeoplasms, Breast1
2Active Not RecruitingTreatmentNeoplasms, Lung1
2CompletedDiagnosticNeoplasms, Breast1
2CompletedTreatmentCarcinoma, Squamous Cell of Head and Neck2
2CompletedTreatmentGliomas1
2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)7
2CompletedTreatmentLung Cancers1
2CompletedTreatmentMetastatic Colorectal Cancers1
2CompletedTreatmentNeoplasms1
2CompletedTreatmentNeoplasms Metastasis / Neoplasms, Breast1
2CompletedTreatmentNeoplasms, Breast3
2CompletedTreatmentNeoplasms, Colorectal2
2CompletedTreatmentNeoplasms, Head and Neck / Squamous Cell Carcinoma (SCC)1
2CompletedTreatmentProstatic Neoplasms1
2CompletedTreatmentRefractory Cancer1
2CompletedTreatmentUnilateral HER2 Positive Breast Cancer1
2Not Yet RecruitingTreatmentChordomas1
2Not Yet RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2Not Yet RecruitingTreatmentNeoplasms, Head and Neck1
2RecruitingTreatmentAdvanced Malignant Neoplasm / Advanced Malignant Solid Neoplasm / Bladder Carcinoma / Carcinoma, Breast / Carcinoma, Colorectal / Carcinoma, Pancreatic / Cervical Carcinoma / Colon Carcinoma / Endometrial Carcinoma / Gastric Carcinoma / Gliomas / Head and Neck Carcinoma / Liver and Intrahepatic Bile Duct Carcinoma / Lung, Carcinoma / Malignant Lymphomas / Malignant Uterine Neoplasm / Melanoma / Oesophageal Carcinoma / Ovarian Carcinoma / Plasma Cell Myeloma / Prostate Cancer / Rectal Carcinoma / Recurrent Bladder Carcinoma / Recurrent Breast Carcinoma / Recurrent Cervical Carcinoma / Recurrent Colon Carcinoma / Recurrent Colorectal Carcinoma / Recurrent Esophageal Carcinoma / Recurrent Gastric Carcinoma / Recurrent Gliomas / Recurrent Head and Neck Carcinoma / Recurrent Liver Carcinoma / Recurrent Lung Carcinoma / Recurrent Lymphoma / Recurrent Malignant Solid Neoplasm / Recurrent Melanoma / Recurrent Ovarian Carcinoma / Recurrent Pancreatic Carcinoma / Recurrent Plasma Cell Myeloma / Recurrent Prostate Carcinoma / Recurrent Rectal Carcinoma / Recurrent Skin Carcinoma / Recurrent Solid Neoplasm / Recurrent Thyroid Gland Carcinoma / Recurrent Uterine Corpus Carcinoma / Refractory Lymphomas / Refractory Malignant Neoplasm / Refractory Malignant Solid Neoplasm / Refractory Plasma Cell Myeloma / Renal Carcinoma / Skin Carcinoma / Solid Neoplasms / Thyroid Gland Carcinoma / Uterine Corpus Cancer1
2RecruitingTreatmentCarcinoma, Squamous Cell of Head and Neck1
2RecruitingTreatmentDistal Urethral Cancer / Metastatic Bladder Cancer / Proximal Urethral Cancer / Recurrent Bladder Cancer / Recurrent Urethral Cancer / Stage III Bladder Cancer / Stage III Urethral Cancer / Stage IV Urethral Cancer / Ureteral Cancer1
2RecruitingTreatmentEsophageal Cancers / Malignant Neoplasm of Stomach1
2RecruitingTreatmentGastroesophageal Junction Cancer / Malignant Neoplasm of Stomach1
2RecruitingTreatmentGastrointestinal Carcinoma, Non-colon / Non-Small Cell Lung Carcinoma (NSCLC) / Transitional Cell Carcinoma / Upper Aerodigestive Tract Carcinoma1
2RecruitingTreatmentHER2/Neu+ Uterine Serous Carcinoma1
2RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)3
2RecruitingTreatmentLung Cancers1
2RecruitingTreatmentPenile Squamous Cell Carcinoma (PSCC)1
2RecruitingTreatmentRare Tumor / Refractory Tumors1
2RecruitingTreatmentSquamous Cell Cancers of the Head and Neck1
2RecruitingTreatmentSquamous Cell Carcinoma of Esophagus1
2RecruitingTreatmentTriple Negative Breast Cancer (TNBC)1
2RecruitingTreatmentTumors, Solid1
2RecruitingTreatmentUrologic Neoplasms1
2SuspendedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2TerminatedTreatmentBreast Cancer Metastatic1
2TerminatedTreatmentLung Cancers1
2TerminatedTreatmentNeoplasms1
2TerminatedTreatmentNon-small-cell Lung Cancer With Somatic EGFR Mutations1
2Unknown StatusTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2WithdrawnTreatmentEsophageal Cancers / Gastrooesophageal Cancer / Her-2 Positive Gastric Cancer1
2WithdrawnTreatmentLung Cancers1
2WithdrawnTreatmentSmall Cell Lung Carcinoma1
2, 3RecruitingTreatmentRecurrent Non-Small Cell Lung Carcinoma / Stage IV Non-Small Cell Lung Cancer1
3Active Not RecruitingTreatmentHead and Neck Squamous Cell Carcinoma (HNSCC)1
3Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
3Active Not RecruitingTreatmentNeoplasms, Head and Neck1
3CompletedTreatmentAdenocarcinomas / Lung Cancer Non-Small Cell Cancer (NSCLC)2
3CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)6
3CompletedTreatmentNeoplasms, Breast1
3CompletedTreatmentNeoplasms, Head and Neck / Squamous Cell Carcinoma (SCC)1
3TerminatedTreatmentNeoplasms, Head and Neck2
4Active Not RecruitingTreatmentErbB Receptors / Lung Cancer Non-Small Cell Cancer (NSCLC)1
4CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
4TerminatedTreatmentErbB Receptors / Lung Cancer Non-Small Cell Cancer (NSCLC)1
Not AvailableActive Not RecruitingNot AvailableLung Cancer Non-Small Cell Cancer (NSCLC)1
Not AvailableApproved for MarketingNot AvailableLung Cancer Non-Small Cell Cancer (NSCLC)3
Not AvailableCompletedNot AvailableLung Cancer Non-Small Cell Cancer (NSCLC)2
Not AvailableCompletedNot AvailableNeoplasms1
Not AvailableCompletedTreatmentEGFR Mutations / Lung Cancer Non-Small Cell Cancer (NSCLC)1
Not AvailableRecruitingNot AvailableLung Cancer Non-Small Cell Cancer (NSCLC)1
Not AvailableRecruitingOtherEGFR Gene Mutations / Non-Small Cell Adenocarcinoma / Tyrosine kinase mutation1
Not AvailableUnknown StatusDiagnosticEGFR Mutation Positive Non-small Cell Lung Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral20 mg/1
Tablet, film coatedOral30 mg/1
Tablet, film coatedOral40 mg/1
TabletOral20 mg
TabletOral30 mg
TabletOral40 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6251912No1998-07-292018-07-29Us
US8426586No2009-10-102029-10-10Us
USRE43431No2002-01-222022-01-22Us
US8545884No2009-12-192029-12-19Us
US9539258No2006-11-092026-11-09Us
US10004743No2010-07-052030-07-05Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0128 mg/mLALOGPS
logP3.77ALOGPS
logP3.76ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)12.49ChemAxon
pKa (Strongest Basic)8.81ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area88.61 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity131.38 m3·mol-1ChemAxon
Polarizability50.07 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.8717
Caco-2 permeable-0.5342
P-glycoprotein substrateSubstrate0.744
P-glycoprotein inhibitor IInhibitor0.6776
P-glycoprotein inhibitor IIInhibitor0.9036
Renal organic cation transporterNon-inhibitor0.7154
CYP450 2C9 substrateNon-substrate0.7919
CYP450 2D6 substrateNon-substrate0.8034
CYP450 3A4 substrateSubstrate0.7504
CYP450 1A2 substrateNon-inhibitor0.5236
CYP450 2C9 inhibitorNon-inhibitor0.7294
CYP450 2D6 inhibitorNon-inhibitor0.7625
CYP450 2C19 inhibitorNon-inhibitor0.5877
CYP450 3A4 inhibitorNon-inhibitor0.6486
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7096
Ames testNon AMES toxic0.5695
CarcinogenicityNon-carcinogens0.8692
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5643 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8956
hERG inhibition (predictor II)Inhibitor0.7228
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
show 14 more
Substituents
Quinazolinamine / N-arylamide / Aniline or substituted anilines / Alkyl aryl ether / Halobenzene / Fluorobenzene / Aminopyrimidine / Chlorobenzene / Aryl chloride / Imidolactam
show 31 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organofluorine compound, tertiary amino compound, aromatic ether, enamide, furans, monochlorobenzenes, quinazolines (CHEBI:61390)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Ubiquitin protein ligase binding
Specific Function
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TG...
Gene Name
EGFR
Uniprot ID
P00533
Uniprot Name
Epidermal growth factor receptor
Molecular Weight
134276.185 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transmembrane signaling receptor activity
Specific Function
Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, alt...
Gene Name
ERBB2
Uniprot ID
P04626
Uniprot Name
Receptor tyrosine-protein kinase erbB-2
Molecular Weight
137909.27 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mamma...
Gene Name
ERBB4
Uniprot ID
Q15303
Uniprot Name
Receptor tyrosine-protein kinase erbB-4
Molecular Weight
146806.865 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da

Drug created on July 17, 2013 15:59 / Updated on October 15, 2018 04:36