ICOTINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H21N3O4
Molecular Weight	391.4198
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C#CC1=CC(NC2=NC=NC3=C2C=C4OCCOCCOCCOC4=C3)=CC=C1

InChI

InChIKey=QQLKULDARVNMAL-UHFFFAOYSA-N

InChI=1S/C22H21N3O4/c1-2-16-4-3-5-17(12-16)25-22-18-13-20-21(14-19(18)23-15-24-22)29-11-9-27-7-6-26-8-10-28-20/h1,3-5,12-15H,6-11H2,(H,23,24,25)

HIDE SMILES / InChI

Description
Sources: https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=717145 | http://www.lillyasiaventures.com/en/home.asp?lm_id=13&lm_id_2=15&id=9 | https://www.ncbi.nlm.nih.gov/pubmed/26831237 | https://www.ncbi.nlm.nih.gov/pubmed/28054523 | https://www.ncbi.nlm.nih.gov/pubmed/26980473 | http://betapharma.com/wp-content/uploads/2016/04/APLCC-Poster-final.pdf

Icotinib is an orally available quinazoline-based inhibitor of epidermal growth factor receptor. It selectively inhibits the wild-type and several mutated forms of EGFR tyrosine kinase. The major organ of icotinib metabolism is the liver, with the primarily enzymes being CYP2C19 and CYP3A4 from the cytochrome P450 monooxygenase system. Icotinib Hydrochloride was approved for the treatment of patients with advanced stage Nonsmall cell lung cancer by the State Food and Drug Administration (SFDA) of China. The major drug related adverse reactions of the traditional cytotoxic agents include rash, diarrhea, severe bone marrow suppression, neuropathy, hair loss, and gastrointestinal reactions. Icotinib is under investigation as an active agent against other EGFR mutation-positive cancers, like lung adenocarcinoma, oesophageal cancer, nasopharyngeal cancer and others.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Epidermal growth factor receptor erbB1 58 Target ID: CHEMBL203 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22112293	Inhibitor 8297	5.0 nM [IC50]
Cytochrome P450 2C19 51 Target ID: CHEMBL3622 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26831237	Substrate 661
Cytochrome P450 3A4 127 Target ID: CHEMBL340 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26831237	Substrate 661

Conditions

Condition	Modality	Highest Phase	Product
Non-small cell lung cancer 206 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24836053	Primary	Approved 8429	Conmana Approved Use Icotinib hydrochloride is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) indicated for non-small cell lung cancer. Launch Date 1.30731842E12
Lung adenocarcinoma 8 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27822065 https://www.ncbi.nlm.nih.gov/pubmed/28054523	Primary	Phase IV 63	Unknown Approved Use Unknown
Esophageal cancer 12 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27013591 https://www.ncbi.nlm.nih.gov/pubmed/26980473	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
0.728 mg/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24488324	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ICOTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
3.22 mg × h/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24488324	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ICOTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
6.02 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24488324	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ICOTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
1.5% EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24488324	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ICOTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
125 mg 3 times / day multiple, oral Recommended Dose: 125 mg, 3 times / day Route: oral Route: multiple Dose: 125 mg, 3 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28945850/	unhealthy, Median age 56 years n = 147 Health Status: unhealthy Condition: lung adenocarcinoma Age Group: Median age 56 years Sex: M+F Population Size: 147 Sources: https://pubmed.ncbi.nlm.nih.gov/28945850/	Other AEs: Leukopenia, ALT increased... Other AEs: Leukopenia (grade 3-4, 0.7%) ALT increased (grade 3-4, 2%) Aspartate aminotransferase increased (grade 3-4, 2.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/28945850/
500 mg 3 times / day multiple, oral MTD Dose: 500 mg, 3 times / day Route: oral Route: multiple Dose: 500 mg, 3 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27789778/	unhealthy, Median age 57 years n = 6 Health Status: unhealthy Condition: Advanced Non-Small Cell Lung Cancer Age Group: Median age 57 years Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/27789778/	DLT: Rash... Dose limiting toxicities: Rash (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/27789778/
125 mg 3 times / day multiple, oral Recommended Dose: 125 mg, 3 times / day Route: oral Route: multiple Dose: 125 mg, 3 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/23948351/	unhealthy, Median age 57 years n = 200 Health Status: unhealthy Condition: non-small-cell lung cancer Age Group: Median age 57 years Sex: M+F Population Size: 200 Sources: https://pubmed.ncbi.nlm.nih.gov/23948351/	Other AEs: Rash, Pain... Other AEs: Rash (grade 3-4, <1%) Pain (grade 3-4, 2%) Transaminases increased (grade 3-4, 1%) Nausea (grade 3-4, <1%) Sources: https://pubmed.ncbi.nlm.nih.gov/23948351/
125 mg 3 times / day multiple, oral Recommended Dose: 125 mg, 3 times / day Route: oral Route: multiple Dose: 125 mg, 3 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28734822/	unhealthy, Median age 57 years n = 85 Health Status: unhealthy Condition: non-small-cell lung cancer Age Group: Median age 57 years Sex: M+F Population Size: 85 Sources: https://pubmed.ncbi.nlm.nih.gov/28734822/	Other AEs: ALT increased, Aspartate aminotransferase increased... Other AEs: ALT increased (grade 3-4, 1%) Aspartate aminotransferase increased (grade 3-4, 1%) Impaired liver function (grade 3-4, 1%) Leucopenia (grade 3-4, 1%) Neutropenia (grade 3-4, 1%) Dizziness (grade 3-4, 1%) Numbness of limbs (grade 3-4, 2%) Sources: https://pubmed.ncbi.nlm.nih.gov/28734822/
625 mg 3 times / day multiple, oral Studied dose Dose: 625 mg, 3 times / day Route: oral Route: multiple Dose: 625 mg, 3 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27789778/	unhealthy, Median age 57 years n = 6 Health Status: unhealthy Condition: Advanced Non-Small Cell Lung Cancer Age Group: Median age 57 years Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/27789778/	DLT: Rash, Hand and foot syndrome... Dose limiting toxicities: Rash (grade 3, 16.7%) Hand and foot syndrome (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/27789778/
125 mg 3 times / day multiple, oral Recommended Dose: 125 mg, 3 times / day Route: oral Route: multiple Dose: 125 mg, 3 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21144613/	unhealthy, Median age 58 years n = 6 Health Status: unhealthy Condition: non-small-cell lung cancer Age Group: Median age 58 years Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21144613/	Other AEs: Mouth ulceration... Other AEs: Mouth ulceration (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/21144613/
100 mg 3 times / day multiple, oral Studied dose Dose: 100 mg, 3 times / day Route: oral Route: multiple Dose: 100 mg, 3 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21144613/	unhealthy, Median age 58 years n = 13 Health Status: unhealthy Condition: non-small-cell lung cancer Age Group: Median age 58 years Sex: M+F Population Size: 13 Sources: https://pubmed.ncbi.nlm.nih.gov/21144613/	Other AEs: Transaminases increased... Other AEs: Transaminases increased (grade 3, 7.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/21144613/
1075 mg 1 times / day single, oral Highest studied dose Dose: 1075 mg, 1 times / day Route: oral Route: single Dose: 1075 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24488324/	healthy n = 8 Health Status: healthy Sex: M Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/24488324/	Sources: https://pubmed.ncbi.nlm.nih.gov/24488324/

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	substrate 1037	substrate 1217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
UGT1A1 204 CYP1A2 1524 BCRP 699	CYP1A2 1054 CYP2B6 664 CYP2C8 693 CYP2C19 991 CYP3A5 395

Drug as perpetrator

Target	Modality	Activity
UGT1A1 254	inhibitor 3277 Sources: https://www.sciencedirect.com/science/article/pii/S2211383517301363 Page: -	yes [IC50 8.76 uM]
BCRP 773	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147343/ Page: -	yes
CYP1A2 1692	inhibitor 3277 Sources: https://www.dovepress.com/comparative-review-of-drug-drug-interactions-with-epidermal-growth-fac-peer-reviewed-fulltext-article-OTT Page: -	yes

Drug as victim

Target	Modality	Activity
CYP3A4 1737	substrate 3367 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0022354917308778?via%3Dihub Page: -	major
CYP2B6 664	substrate 3367 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0022354917308778?via%3Dihub Page: -	no
CYP2C19 991	substrate 3367 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0022354917308778?via%3Dihub Page: -	no
CYP2C8 693	substrate 3367 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0022354917308778?via%3Dihub Page: -	no
CYP2C9 1037	substrate 3367 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0022354917308778?via%3Dihub Page: -	no
CYP2D6 1217	substrate 3367 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0022354917308778?via%3Dihub Page: -	no
CYP1A2 1054	substrate 3367 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0022354917308778?via%3Dihub Page: -	yes
CYP3A5 395	substrate 3367 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0022354917308778?via%3Dihub Page: -	yes

PubMed

Title	Date	PubMed
Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors.	2011 Aug	21144613
Synthesis and biological evaluation of crown ether fused quinazoline analogues as potent EGFR inhibitors.	2012 Oct 1	22959248

Patents

Sample Use Guides

In Vivo Use Guide

125 mg q8h/day

Route of Administration: Oral

In Vitro Use Guide

Icotinib induces G1 phase cell cycle arrest and apoptosis in HCC827 cells. There was an increase in the number of cells in G1 phase after exposure to 0.01 and 0.1 uM icotinib for 24 h. The percentage of cells in G1 phase increased from 45.41 to 68.41 and 78.30, respectively. Furthermore, the percentages of apoptotic cells were elevated from 4.26% to 6.31% and 18.85%, after treatment with 0.01 and 0.1 uM icotinib.

Name

Type

Language

ICOTINIB

Common Name

English

Icotinib [WHO-DD]

Common Name

English

BPI-2009

Common Name

English

(1,4,7,10)TETRAOXACYCLODODECINO(2,3-G)QUINAZOLIN-4-AMINE, N-(3-ETHYNYLPHENYL)-7,8,10,11,13,14-HEXAHYDRO-

Systematic Name

English

Classification Tree Code System Code

WHO-ATC

L01XE48