AXITINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H18N4OS
Molecular Weight	386.47
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

SMILES

CNC(=O)C1=CC=CC=C1SC2=CC3=C(C=C2)C(\C=C\C4=CC=CC=N4)=NN3

InChI

InChIKey=RITAVMQDGBJQJZ-FMIVXFBMSA-N

InChI=1S/C22H18N4OS/c1-23-22(27)18-7-2-3-8-21(18)28-16-10-11-17-19(25-26-20(17)14-16)12-9-15-6-4-5-13-24-15/h2-14H,1H3,(H,23,27)(H,25,26)/b12-9+

HIDE SMILES / InChI

Molecular Formula	C22H18N4OS
Molecular Weight	386.47
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

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

Description

Axitinib (trade name Inlyta) is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types. Axitinib has been shown to inhibit receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. VEGF-mediated endothelial cell proliferation and survival were inhibited by axitinib in vitro and in mouse models. It was approved by the U.S. Food and Drug Administration.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Vascular endothelial growth factor receptor 1 41	Inhibitor 8,297	0.1 nM [IC50]
Vascular endothelial growth factor receptor 2 104	Inhibitor 8,297	0.2 nM [IC50]
Vascular endothelial growth factor receptor 3 41	Inhibitor 8,297	0.3 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Renal cell carcinoma 31	Secondary		Approved 8,429	INLYTA

C_max

Value	Dose	Analyte	Population
162 ng/mL	20 mg 2 times / day steady-state, oral	AXITINIB plasma	Homo sapiens
82 ng/mL	15 mg 1 times / day steady-state, oral	AXITINIB plasma	Homo sapiens
27.8 ng/mL	5 mg single, oral	AXITINIB plasma	Homo sapiens
27.8 ng/mL	5 mg 2 times / day steady-state, oral	AXITINIB plasma	Homo sapiens
51.1 ng/mL	5 mg single, oral	AXITINIB plasma	Homo sapiens
32.2 ng/mL	5 mg single, oral	AXITINIB blood	Homo sapiens
52.7 ng/mL	5 mg single, oral	AXITINIB blood	Homo sapiens
28.8 ng/mL	5 mg single, oral	AXITINIB blood	Homo sapiens

AUC

Value	Dose	Analyte	Population
2171 ng × h/mL	20 mg 2 times / day steady-state, oral	AXITINIB plasma	Homo sapiens
717 μg × h/mL	15 mg 1 times / day steady-state, oral	AXITINIB plasma	Homo sapiens
265 ng × h/mL	5 mg single, oral	AXITINIB plasma	Homo sapiens
265 ng × h/mL	5 mg 2 times / day steady-state, oral	AXITINIB plasma	Homo sapiens
187 ng × h/mL	5 mg single, oral	AXITINIB plasma	Homo sapiens
160.3 ng × h/mL	5 mg single, oral	AXITINIB blood	Homo sapiens
206.8 ng × h/mL	5 mg single, oral	AXITINIB blood	Homo sapiens
162 ng × h/mL	5 mg single, oral	AXITINIB blood	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
4.8 h	20 mg 2 times / day steady-state, oral	AXITINIB plasma	Homo sapiens
4.6 h	15 mg 1 times / day steady-state, oral	AXITINIB plasma	Homo sapiens
9.4 h	5 mg single, oral	AXITINIB plasma	Homo sapiens
5.4 h	5 mg single, oral	AXITINIB blood	Homo sapiens
7 h	5 mg single, oral	AXITINIB blood	Homo sapiens
3 h	5 mg single, oral	AXITINIB blood	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
1%	5 mg single, oral		AXITINIB plasma	Homo sapiens
1%	5 mg 2 times / day steady-state, oral		AXITINIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
5 mg 2 times / day steady, oral	unhealthy, 62 years (range: 20-82 years)	Disc. AE: Disease progression, Fatigue...
30 mg 2 times / day steady, oral Highest studied dose	unhealthy
5 mg 2 times / day steady, oral MTD	unhealthy	DLT: Stomatitis...
15 mg 1 times / day steady, oral	unhealthy	DLT: Hypertension, Stomatitis...
20 mg 2 times / day steady, oral	unhealthy	DLT: Hypertension, Hemoptysis...

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AEs

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AE	Significance	Dose	Population
Altered state of consciousness	1 patient Disc. AE	5 mg 2 times / day steady, oral	unhealthy, 62 years (range: 20-82 years)
Anemia	1 patient Disc. AE	5 mg 2 times / day steady, oral	unhealthy, 62 years (range: 20-82 years)
Ascites	1 patient Disc. AE	5 mg 2 times / day steady, oral	unhealthy, 62 years (range: 20-82 years)
Blood creatinine increased	1 patient Disc. AE	5 mg 2 times / day steady, oral	unhealthy, 62 years (range: 20-82 years)
Cerebral hemorrhage	1 patient Disc. AE	5 mg 2 times / day steady, oral	unhealthy, 62 years (range: 20-82 years)

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587 inducer 781	inhibitor 1,767	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2A6 707 CYP2C8 911 CYP2C19 1,478 CYP2E1 882 P-gp 1,461 UGT1A1 204	CYP3A5 395 CYP1A2 1,054 CYP2C19 991 UGT1A1 418 P-gp 1,537 UGT1A3 422 UGT1A4 347 UGT1A6 307 UGT1A7 236 UGT1A8 283 UGT1A9 380 UGT1A10 291 UGT2B4 249 UGT2B7 389 UGT2B15 203 UGT2B17 213 BCRP 561 OATP1B1 406 OATP1B3 350	CYP1A 56

Drug as perpetrator

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Target	Modality	Activity
CYP1A 121	inducer 1,573	no
CYP2A6 739	inhibitor 3,277	no
CYP2C19 1,553	inhibitor 3,277	no
CYP2D6 1,891	inhibitor 3,277	no
CYP2E1 970	inhibitor 3,277	no

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,737	substrate 3,367	major	yes (co-administration study)
CYP3A5 395	substrate 3,367	major	yes (co-administration study)
CYP1A2 1,054	substrate 3,367	minor
CYP2C19 991	substrate 3,367	minor	no (pharmacogenomic study)
UGT1A1 418	substrate 3,367	minor	no (pharmacogenomic study)

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:66910	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:66910
ChemicalBook	CB81011728	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB81011728
eMolecules	26951384	https://www.emolecules.com/cgi-bin/more?vid=26951384
MolPort	MolPort-006-392-413	https://www.molport.com/shop/molecule-link/MolPort-006-392-413
Selleck Chemicals	Axitinib	http://www.selleckchem.com/products/Axitinib.html

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PubMed

Title	Date	PubMed
No data available in table

Patents

Sample Use Guides

In Vivo Use Guide

5 mg orally twice daily

Route of Administration: Oral

In Vitro Use Guide

Transfected or endogenous RTK-expressing cells were treated by axitinib with range of concentration from 0.01 nM to 10 uM. In transfected or endogenous RTK-expressing cells, axitinib potently blocked growth factor-stimulated phosphorylation of VEGFR-2 and VEGFR-3 with average IC50 values of 0.2 and 0.1 to 0.3 nmol/L, respectively. Cellular activity against VEGFR-1 was 1.2 nmol/L.