Details of the Drug

General Information of Drug (ID: DMSTA36)

Drug Name

Intedanib

Synonyms

Nintedanib; Vargatef; 656247-17-5; BIBF-1120; BIBF 1120; 928326-83-4; BIBF1120; Nintedanib (BIBF 1120); OFEV; UNII-G6HRD2P839; (Z)-methyl 3-((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenylamino)(phenyl)methylene)-2-oxoindoline-6-carboxylate; G6HRD2P839; CHEBI:85164; 1160294-26-7; Methyl (3z)-3-{[(4-{methyl[(4-Methylpiperazin-1-Yl)acetyl]amino}phenyl)amino](Phenyl)methylidene}-2-Oxo-2,3-Dihydro-1h-Indole-6-Carboxylate

Indication

Disease Entry	ICD 11	Status	REF
Colorectal cancer	2B91.Z	Approved	[1]
Idiopathic pulmonary fibrosis	CB03.4	Approved	[2]
Mesothelioma	2C51.2	Phase 3	[3]
Non-small-cell lung cancer	2C25.Y	Phase 3	[4]
Ovarian cancer	2C73	Phase 2	[4]
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Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 1

Molecular Weight (mw)

539.6

Logarithm of the Partition Coefficient (xlogp)

4.3

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

Bioavailability: The bioavailability of drug is 4.7% [5]
Clearance: The renal clearance of drug is 20 mL/min [6]
Elimination: Nintedanib is eliminated primarily via fecal and biliary excretion, with 93.4% of radio labelled nintedanib found in feces within 120 hours following administration [6]
Half-life: The concentration or amount of drug in body reduced by one-half in 10 - 15 hours [7]
Metabolism: The drug is metabolized via the hydrolytic cleavage by esterases to its principle metabolite BIBF 1202 [5]
Unbound Fraction: The unbound fraction of drug in plasma is 0.02% [8]
Vd: The volume of distribution (Vd) of drug is 1050 L [5]

Chemical Identifiers

Formula: C31H33N5O4
IUPAC Name: methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate
Canonical SMILES: CN1CCN(CC1)CC(=O)N(C)C2=CC=C(C=C2)N=C(C3=CC=CC=C3)C4=C(NC5=C4C=CC(=C5)C(=O)OC)O
InChI: 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/h4-14,19,33,38H,15-18,20H2,1-3H3
InChIKey: CPMDPSXJELVGJG-UHFFFAOYSA-N

Cross-matching ID

PubChem CID: 135423438
ChEBI ID: CHEBI:85164
CAS Number: 656247-17-5
TTD ID: D09HNV
VARIDT ID: DR00137

Repurposed Drugs (RPD)

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Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Fibroblast growth factor receptor 1 (FGFR1)	TTRLW2X	FGFR1_HUMAN	Modulator	[1]
Fms-like tyrosine kinase 3 (FLT-3)	TTGJCWZ	FLT3_HUMAN	Inhibitor	[1]
Platelet-derived growth factor receptor (PDGFR)	TTI2WET	NOUNIPROTAC	Modulator	[1]
Vascular endothelial growth factor receptor (VEGFR)	TTVJ1D8	NOUNIPROTAC	Modulator	[1]

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Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Molecular Expression Atlas of This Drug

The Studied Disease

Colorectal cancer

ICD Disease Classification

2B91.Z

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Fibroblast growth factor receptor 1 (FGFR1)	DTT	FGFR1	5.16E-02	1.24E-03	4.64E-03
Fms-like tyrosine kinase 3 (FLT-3)	DTT	FLT3	2.64E-120	3.41	4.96
P-glycoprotein 1 (ABCB1)	DTP	P-GP	4.70E-06	-5.80E-02	-1.98E-01

Molecular Expression Atlas (MEA)

MEA Detail

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Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Intedanib (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Arn-509	DMT81LZ	Moderate	Accelerated clearance of Intedanib due to the transporter induction by Arn-509.	Acute myeloid leukaemia [2A60]	[10]
Gilteritinib	DMTI0ZO	Moderate	Decreased clearance of Intedanib due to the transporter inhibition by Gilteritinib.	Acute myeloid leukaemia [2A60]	[11]
Erdafitinib	DMI782S	Moderate	Decreased clearance of Intedanib due to the transporter inhibition by Erdafitinib.	Bladder cancer [2C94]	[12]
Pexidartinib	DMS2J0Z	Major	Increased risk of hepatotoxicity by the combination of Intedanib and Pexidartinib.	Bone/articular cartilage neoplasm [2F7B]	[13]
Tucatinib	DMBESUA	Moderate	Decreased clearance of Intedanib due to the transporter inhibition by Tucatinib.	Breast cancer [2C60-2C6Y]	[14]
PF-04449913	DMSB068	Moderate	Decreased clearance of Intedanib due to the transporter inhibition by PF-04449913.	Chronic myelomonocytic leukaemia [2A40]	[10]
Lumacaftor	DMCLWDJ	Major	Accelerated clearance of Intedanib due to the transporter induction by Lumacaftor.	Cystic fibrosis [CA25]	[15]
Tazemetostat	DMWP1BH	Moderate	Increased risk of bleeding by the combination of Intedanib and Tazemetostat.	Follicular lymphoma [2A80]	[14]
PF-06463922	DMKM7EW	Major	Increased metabolism of Intedanib caused by PF-06463922 mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[14]
Selpercatinib	DMZR15V	Moderate	Decreased metabolism of Intedanib caused by Selpercatinib mediated inhibition of CYP450 enzyme.	Lung cancer [2C25]	[14]
Calaspargase pegol	DMQZBXI	Moderate	Increased risk of hepatotoxicity by the combination of Intedanib and Calaspargase pegol.	Malignant haematopoietic neoplasm [2B33]	[16]
IPI-145	DMWA24P	Moderate	Decreased metabolism of Intedanib caused by IPI-145 mediated inhibition of CYP450 enzyme.	Mature B-cell leukaemia [2A82]	[17]
Lasmiditan	DMXLVDT	Moderate	Decreased clearance of Intedanib due to the transporter inhibition by Lasmiditan.	Migraine [8A80]	[18]
Fedratinib	DM4ZBK6	Moderate	Increased risk of bleeding by the combination of Intedanib and Fedratinib.	Myeloproliferative neoplasm [2A20]	[14]
Rolapitant	DM8XP26	Moderate	Decreased clearance of Intedanib due to the transporter inhibition by Rolapitant.	Nausea/vomiting [MD90]	[19]
Abametapir	DM2RX0I	Moderate	Decreased metabolism of Intedanib caused by Abametapir mediated inhibition of CYP450 enzyme.	Pediculosis [1G00]	[20]
Lefamulin	DME6G97	Moderate	Decreased metabolism of Intedanib caused by Lefamulin mediated inhibition of CYP450 enzyme.	Pneumonia [CA40]	[21]
Telotristat ethyl	DMDIYFZ	Moderate	Increased metabolism of Intedanib caused by Telotristat ethyl mediated induction of CYP450 enzyme.	Small intestine developmental anomaly [DA90]	[10]
Larotrectinib	DM26CQR	Moderate	Decreased metabolism of Intedanib caused by Larotrectinib mediated inhibition of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[11]
Fostamatinib	DM6AUHV	Moderate	Decreased metabolism of Intedanib caused by Fostamatinib mediated inhibition of CYP450 enzyme.	Thrombocytopenia [3B64]	[22]
Betrixaban	DM2C4RF	Moderate	Increased risk of bleeding by the combination of Intedanib and Betrixaban.	Venous thromboembolism [BD72]	[14]
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References

1	2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
2	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
3	Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
4	URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5936).
5	Beedham C, Miceli JJ, Obach RS: Ziprasidone metabolism, aldehyde oxidase, and clinical implications. J Clin Psychopharmacol. 2003 Jun;23(3):229-32. doi: 10.1097/01.jcp.0000084028.22282.f2.
6	FDA Approved Drugs: Nintedanib
7	EMA Approved Drugs: Nintedanib
8	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
9	Effects of Ketoconazole and Rifampicin on the Pharmacokinetics of Nintedanib in Healthy Subjects. Eur J Drug Metab Pharmacokinet. 2018 Oct;43(5):533-541.
10	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
11	Cerner Multum, Inc. "Australian Product Information.".
12	Product Information. Balversa (erdafitinib). Janssen Products, LP, Horsham, PA.
13	Product Information. Turalio (pexidartinib). Daiichi Sankyo, Inc., Parsippany, NJ.
14	Product Information. Ofev (nintedanib). Boehringer Ingelheim, Ridgefield, CT.
15	Canadian Pharmacists Association.
16	Al-Nawakil C, Willems L, Mauprivez C, et.al "Successful treatment of l-asparaginase-induced severe acute hepatotoxicity using mitochondrial cofactors." Leuk Lymphoma 55 (2014): 1670-4. [PMID: 24090500]
17	Product Information. Copiktra (duvelisib). Verastem, Inc., Needham, MA.
18	Product Information. Reyvow (lasmiditan). Lilly, Eli and Company, Indianapolis, IN.
19	Product Information. Varubi (rolapitant). Tesaro Inc., Waltham, MA.
20	Product Information. Xeglyze (abametapir topical). Dr. Reddy's Laboratories Inc, Upper Saddle River, NJ.
21	Product Information. Fycompa (perampanel). Eisai Inc, Teaneck, NJ.
22	Product Information. Tavalisse (fostamatinib). Rigel Pharmaceuticals, South San Francisco, CA.