NINTEDANIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C31H33N5O4
Molecular Weight	539.6248
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

SMILES

COC(=O)C1=CC2=C(C=C1)\C(C(=O)N2)=C(\NC3=CC=C(C=C3)N(C)C(=O)CN4CCN(C)CC4)C5=CC=CC=C5

InChI

InChIKey=XZXHXSATPCNXJR-ZIADKAODSA-N

InChI=1S/C31H33N5O4/c1-34-15-17-36(18-16-34)20-27(37)35(2)24-12-10-23(11-13-24)32-29(21-7-5-4-6-8-21)28-25-14-9-22(31(39)40-3)19-26(25)33-30(28)38/h4-14,19,32H,15-18,20H2,1-3H3,(H,33,38)/b29-28-

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Description

Nintedanib is a receptor tyrosine kinase inhibitor with potential antiangiogenic and antineoplastic activities. It is the only kinase inhibitor drug approved to treat idiopathic pulmonary fibrosis. that targets multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Nintedanib inhibits the following RTKs: platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, and Fms-like tyrosine kinase-3 (FLT3). Among them, FGFR, PDGFR, and VEGFR have been implicated in IPF pathogenesis. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signaling which is crucial for the proliferation, migration, and transformation of fibroblasts representing essential mechanisms of the IPF pathology.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Vascular endothelial growth factor receptor 1	Inhibitor	34.0 nM [IC50]
Vascular endothelial growth factor receptor 2	Inhibitor	21.0 nM [IC50]
Vascular endothelial growth factor receptor 3	Inhibitor	13.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Idiopathic pulmonary fibrosis	Primary		Approved	OFEV

C_max

Value	Dose	Co-administered	Analyte	Population
34.8 ng/mL	150 mg 2 times / day steady-state, oral		NINTEDANIB plasma	Homo sapiens
8.4 ng/mL	100 mg single, oral		NINTEDANIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
171 ng × h/mL	150 mg 2 times / day steady-state, oral		NINTEDANIB plasma	Homo sapiens
56.2 ng × h/mL	100 mg single, oral		NINTEDANIB plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
16.3 h	150 mg 2 times / day steady-state, oral	NINTEDANIB plasma	Homo sapiens
9.5 h	150 mg 2 times / day multiple, oral	NINTEDANIB plasma	Homo sapiens
11.7 h	100 mg single, oral	NINTEDANIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
2.2%	150 mg 2 times / day multiple, oral		NINTEDANIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
200 mg 1 times / day steady, oral	unhealthy, 61 years	DLT: Gamma-glutamyltransferase increased...
250 mg 1 times / day steady, oral	unhealthy, 61 years	DLT: Gamma-glutamyltransferase increased...
150 mg 2 times / day steady, oral Recommended	unhealthy, 67 years (range: 42 - 89 years)	Disc. AE: Diarrhea, Nausea...
150 mg 2 times / day steady, oral Recommended	unhealthy, 67 years (range: 42 - 89 years)	Disc. AE: Weight decreased, Alanine aminotransferase increased...
150 mg 2 times / day steady, oral Recommended	unhealthy, 67 years (range: 42 - 89 years)	Disc. AE: Vomiting, Abdominal pain...

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AEs

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AE	Significance	Dose	Population
Gamma-glutamyltransferase increased	grade 3, 1 patient DLT	200 mg 1 times / day steady, oral	unhealthy, 61 years
Gamma-glutamyltransferase increased	grade 3, 1 patient DLT	250 mg 1 times / day steady, oral	unhealthy, 61 years
Decreased appetite	2% Disc. AE	150 mg 2 times / day steady, oral Recommended	unhealthy, 67 years (range: 42 - 89 years)
Nausea	2% Disc. AE	150 mg 2 times / day steady, oral Recommended	unhealthy, 67 years (range: 42 - 89 years)
Diarrhea	5% Disc. AE	150 mg 2 times / day steady, oral Recommended	unhealthy, 67 years (range: 42 - 89 years)

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate inhibitor inducer	inhibitor inducer	inhibitor	inhibitor

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 CYP2A6 CYP2B6 CYP2C8 CYP2C19 CYP2E1 CYP4A11 UGT1A1 UGT2B7 OCT2 OCT1 OAT1 OAT2 MRP2 BCRP P-gp	P-gp UGT1A1 UGT1A7 UGT1A8 UGT1A10 esterase OCT2 MRP2 BCRP OCT1	CYP1A2 CYP2B6 CYP2C8 CYP2C19

Drug as perpetrator

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Target	Modality	Activity	Metabolite
OCT1	inhibitor	no [IC50 16 uM]	BIBF 1202
UGT1A1	inhibitor	no [IC50 24.5 uM]
UGT1A1	inhibitor	no [IC50 24.5 uM]	BIBF 1202
CYP3A4	inhibitor	no [IC50 70.1 uM]
UGT2B7	inhibitor	no [IC50 77.6 uM]

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Drug as victim

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Target	Modality	Activity	Metabolite
esterase	substrate	major
CYP3A4	substrate	minor
BCRP	substrate	no
BCRP	substrate	no	BIBF 1202
MRP2	substrate	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG	inhibitor

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:85164	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:85164
ChemicalBook	CB72510401	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB72510401
ChemicalBook	CB92467147	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB92467147
ChemicalBook	CB92469909	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB92469909
MolPort	MolPort-009-679-380	https://www.molport.com/shop/molecule-link/MolPort-009-679-380

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PubMed

Title	Date	PubMed
Nintedanib: A Review of Its Use in Patients with Idiopathic Pulmonary Fibrosis.	2015 Jul	26063212

Patents

Sample Use Guides

In Vivo Use Guide

150 mg twice daily approximately 12 hours apart taken with food. Recommended dosage in patients with mild hepatic impairment: 100 mg twice daily approximately 12 hours apart taken with food. Consider temporary dose reduction to 100 mg, treatment interruption, or discontinuation for management of adverse reactions. Prior to treatment, conduct liver function tests and a pregnancy test

Route of Administration: Oral

In Vitro Use Guide

10-80 nmol/L resulted in 50% inhibition (EC50) of cell proliferation in human umbilical vascular endothelial cell HUVEC, microvascular skin endothelial cells HMSEC, umbilical artery smooth muscle cells HUASMC

Show entries

Name

Type

Language

NINTEDANIB

Official Name

English

BIBF1120

Code

English

INTEDANIB

Common Name

English

BIBF 1120

Code

English

NINTEDANIB COMPONENT OF OFEV

Brand Name

English

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Classification Tree

Code System

Code

PULMONARY FIBROSIS

EMA ASSESSMENT REPORTS

OFEV (AUTHORISED: IDIOPATHIC PULMONARY FIBROSIS)

Designated/Approved

FDA ORPHAN DRUG

344511

Protein kinase inhibitors

WHO-ATC

L01XE31

Positive

EU-Orphan Drug

EU/3/16/1724

Designated

FDA ORPHAN DRUG

547916

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Code System

Code

Type

Description

DAILYMED

G6HRD2P839

PRIMARY

EVMPD

SUB120728

PRIMARY

MERCK INDEX

m6301

PRIMARY

Merck Index

DRUG CENTRAL

4903

PRIMARY

MESH

C530716

PRIMARY

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ACTIVE MOIETY


					G6HRD2P839

NINTEDANIB

METABOLITE (PARENT)


					GZ544M4ZP6

(3Z)-3-((4-(METHYL-(2-PIPERAZIN-1-YLACETYL)AMINO)ANILINO)-PHENYL-METHYLENE)-2-OXO-INDOLINE-6-CARBOXYLIC ACID

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator