Details of the Drug

General Information of Drug (ID: DMHSY1I)

Drug Name

Regorafenib

Synonyms

Regorafenib; 755037-03-7; BAY 73-4506; Regorafenibum; Stivarga; 4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide; BAY73-4506; Regorafenib (BAY 73-4506); UNII-24T2A1DOYB; 4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide; BAY-73-4506; 24T2A1DOYB; CHEMBL1946170; CHEBI:68647; Stivarga (TN); BAY73-4506 hydrochloride; Regorafenib [USAN:INN]

Indication

Disease Entry	ICD 11	Status	REF
Gastrointestinal stromal tumour	2B5B	Approved	[1]
Metastasis from malignant tumor of colon	N.A.	Approved	[1]
Metastatic colorectal cancer	2B91	Approved	[2]
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Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

482.8

Logarithm of the Partition Coefficient (xlogp)

4.2

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 70.4 mgh/L []
Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 2.5 mg/L []
Absorption Tmax: The time to maximum plasma concentration (Tmax) is 4 h []
Half-life: The concentration or amount of drug in body reduced by one-half in 28 hours [3]
Metabolism: The drug is metabolized via the CYP3A4 and UGT1A9 [4]

Chemical Identifiers

Formula: C21H15ClF4N4O3
IUPAC Name: 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
Canonical SMILES: CNC(=O)C1=NC=CC(=C1)OC2=CC(=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F)F
InChI: InChI=1S/C21H15ClF4N4O3/c1-27-19(31)18-10-13(6-7-28-18)33-12-3-5-17(16(23)9-12)30-20(32)29-11-2-4-15(22)14(8-11)21(24,25)26/h2-10H,1H3,(H,27,31)(H2,29,30,32)
InChIKey: FNHKPVJBJVTLMP-UHFFFAOYSA-N

Cross-matching ID

PubChem CID: 11167602
ChEBI ID: CHEBI:68647
CAS Number: 755037-03-7
DrugBank ID: DB08896
TTD ID: D09GDD
VARIDT ID: DR00136
INTEDE ID: DR1401
ACDINA ID: D00586

Combinatorial Drugs (CBD)

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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
Proto-oncogene c-Ret (RET)	TT4DXQT	RET_HUMAN	Modulator	[5]
Tyrosine-protein kinase Kit (KIT)	TTX41N9	KIT_HUMAN	Modulator	[5]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Modulator	[5]

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Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[6]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[7]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[6]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]

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Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)_{Main DME}	DE4LYSA	CP3A4_HUMAN	Substrate	[9]
UDP-glucuronosyltransferase 1A9 (UGT1A9)_{Main DME}	DE85D2P	UD19_HUMAN	Substrate	[9]

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Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Protein Interaction/Cellular Processes	[10]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Gene/Protein Processing	[11]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Gene/Protein Processing	[11]
E3 ubiquitin-protein ligase XIAP	OT24GP9B	XIAP_HUMAN	Gene/Protein Processing	[11]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Gene/Protein Processing	[11]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Gene/Protein Processing	[11]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Post-Translational Modifications	[11]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Post-Translational Modifications	[11]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Protein Interaction/Cellular Processes	[11]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Gene/Protein Processing	[11]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Molecular Expression Atlas of This Drug

The Studied Disease

Gastrointestinal stromal tumour

ICD Disease Classification

2B5B

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Tyrosine-protein kinase Kit (KIT)	DTT	KIT	2.06E-01	-0.1	-0.14
Vascular endothelial growth factor receptor 2 (KDR)	DTT	KDR	1.98E-01	0.11	0.2
P-glycoprotein 1 (ABCB1)	DTP	P-GP	9.39E-02	1.07E-01	2.80E-01
Breast cancer resistance protein (ABCG2)	DTP	BCRP	9.45E-01	-5.34E-02	-9.01E-02
Multidrug resistance-associated protein 2 (ABCC2)	DTP	MRP2	7.16E-01	-1.28E-02	-6.06E-02
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DTP	OATP1B1	8.15E-01	6.20E-03	5.61E-02
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	1.04E-02	6.29E-02	3.54E-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 Regorafenib (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Remdesivir	DMBFZ6L	Moderate	Increased risk of hepatotoxicity by the combination of Regorafenib and Remdesivir.	1D6YCoronavirus Disease 2019 [1D6YCoronavirus Disease 2019]	[12]
Arn-509	DMT81LZ	Moderate	Increased metabolism of Regorafenib caused by Arn-509 mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[13]
Bedaquiline	DM3906J	Moderate	Increased risk of hepatotoxicity by the combination of Regorafenib and Bedaquiline.	Antimicrobial drug resistance [MG50-MG52]	[14]
Troleandomycin	DMUZNIG	Moderate	Decreased metabolism of Regorafenib caused by Troleandomycin mediated inhibition of CYP450 enzyme.	Bacterial infection [1A00-1C4Z]	[12]
Pexidartinib	DMS2J0Z	Major	Decreased metabolism of Regorafenib caused by Pexidartinib mediated inhibition of CYP450 enzyme.	Bone/articular cartilage neoplasm [2F7B]	[15]
Talazoparib	DM1KS78	Moderate	Decreased clearance of Regorafenib due to the transporter inhibition by Talazoparib.	Breast cancer [2C60-2C6Y]	[16]
Tucatinib	DMBESUA	Moderate	Decreased metabolism of Regorafenib caused by Tucatinib mediated inhibition of CYP450 enzyme.	Breast cancer [2C60-2C6Y]	[12]
Levomilnacipran	DMV26S8	Moderate	Increased risk of bleeding by the combination of Regorafenib and Levomilnacipran.	Chronic pain [MG30]	[17]
Lumacaftor	DMCLWDJ	Moderate	Increased metabolism of Regorafenib caused by Lumacaftor mediated induction of CYP450 enzyme.	Cystic fibrosis [CA25]	[18]
Vortioxetine	DM6F1PU	Moderate	Increased risk of bleeding by the combination of Regorafenib and Vortioxetine.	Depression [6A70-6A7Z]	[17]
Cannabidiol	DM0659E	Moderate	Increased risk of hepatotoxicity by the combination of Regorafenib and Cannabidiol.	Epileptic encephalopathy [8A62]	[19]
Tazemetostat	DMWP1BH	Major	Increased risk of bleeding by the combination of Regorafenib and Tazemetostat.	Follicular lymphoma [2A80]	[19]
Avapritinib	DMK2GZX	Major	Increased risk of bleeding by the combination of Regorafenib and Avapritinib.	Gastrointestinal stromal tumour [2B5B]	[19]
Cobicistat	DM6L4H2	Moderate	Decreased metabolism of Regorafenib caused by Cobicistat mediated inhibition of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[12]
Dolutegravir	DMCZGRE	Minor	Decreased metabolism of Regorafenib caused by Dolutegravir mediated inhibition of UGT.	Human immunodeficiency virus disease [1C60-1C62]	[20]
Berotralstat	DMWA2DZ	Major	Decreased clearance of Regorafenib due to the transporter inhibition by Berotralstat.	Innate/adaptive immunodeficiency [4A00]	[21]
Naloxegol	DML0B41	Minor	Decreased clearance of Regorafenib due to the transporter inhibition by Naloxegol.	Large intestine motility disorder [DB32]	[22]
Ceritinib	DMB920Z	Moderate	Decreased metabolism of Regorafenib caused by Ceritinib mediated inhibition of CYP450 enzyme.	Lung cancer [2C25]	[12]
PF-06463922	DMKM7EW	Moderate	Increased metabolism of Regorafenib caused by PF-06463922 mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[23]
Selpercatinib	DMZR15V	Moderate	Decreased metabolism of Regorafenib caused by Selpercatinib mediated inhibition of CYP450 enzyme.	Lung cancer [2C25]	[24]
Calaspargase pegol	DMQZBXI	Moderate	Increased risk of hepatotoxicity by the combination of Regorafenib and Calaspargase pegol.	Malignant haematopoietic neoplasm [2B33]	[25]
Idelalisib	DM602WT	Moderate	Increased risk of hepatotoxicity by the combination of Regorafenib and Idelalisib.	Mature B-cell leukaemia [2A82]	[26]
GDC-0199	DMH0QKA	Major	Decreased clearance of Regorafenib due to the transporter inhibition by GDC-0199.	Mature B-cell leukaemia [2A82]	[12]
IPI-145	DMWA24P	Moderate	Decreased metabolism of Regorafenib caused by IPI-145 mediated inhibition of CYP450 enzyme.	Mature B-cell leukaemia [2A82]	[27]
Acalabrutinib	DM7GCVW	Major	Increased risk of bleeding by the combination of Regorafenib and Acalabrutinib.	Mature B-cell lymphoma [2A85]	[19]
Ibrutinib	DMHZCPO	Major	Increased risk of bleeding by the combination of Regorafenib and Ibrutinib.	Mature B-cell lymphoma [2A85]	[19]
Ponatinib	DMYGJQO	Major	Increased risk of bleeding by the combination of Regorafenib and Ponatinib.	Mature B-cell lymphoma [2A85]	[19]
Arry-162	DM1P6FR	Major	Increased risk of bleeding by the combination of Regorafenib and Arry-162.	Melanoma [2C30]	[19]
LGX818	DMNQXV8	Major	Increased risk of bleeding by the combination of Regorafenib and LGX818.	Melanoma [2C30]	[19]
Dabrafenib	DMX6OE3	Moderate	Increased metabolism of Regorafenib caused by Dabrafenib mediated induction of CYP450 enzyme.	Melanoma [2C30]	[19]
Ubrogepant	DM749I3	Moderate	Decreased clearance of Regorafenib due to the transporter inhibition by Ubrogepant.	Migraine [8A80]	[28]
Rimegepant	DMHOAUG	Moderate	Decreased clearance of Regorafenib due to the transporter inhibition by Rimegepant.	Migraine [8A80]	[29]
Fedratinib	DM4ZBK6	Major	Increased risk of bleeding by the combination of Regorafenib and Fedratinib.	Myeloproliferative neoplasm [2A20]	[19]
Vorapaxar	DMA16BR	Major	Increased risk of bleeding by the combination of Regorafenib and Vorapaxar.	Myocardial infarction [BA41-BA43]	[19]
Abametapir	DM2RX0I	Moderate	Decreased metabolism of Regorafenib caused by Abametapir mediated inhibition of CYP450 enzyme.	Pediculosis [1G00]	[30]
Lefamulin	DME6G97	Moderate	Decreased metabolism of Regorafenib caused by Lefamulin mediated inhibition of CYP450 enzyme.	Pneumonia [CA40]	[31]
Enzalutamide	DMGL19D	Moderate	Increased metabolism of Regorafenib caused by Enzalutamide mediated induction of CYP450 enzyme.	Prostate cancer [2C82]	[13]
Larotrectinib	DM26CQR	Moderate	Decreased metabolism of Regorafenib caused by Larotrectinib mediated inhibition of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[12]
Fostamatinib	DM6AUHV	Moderate	Decreased clearance of Regorafenib due to the transporter inhibition by Fostamatinib.	Thrombocytopenia [3B64]	[32]
Lusutrombopag	DMH6IKO	Moderate	Decreased clearance of Regorafenib due to the transporter inhibition by Lusutrombopag.	Thrombocytopenia [3B64]	[33]
Betrixaban	DM2C4RF	Major	Increased risk of bleeding by the combination of Regorafenib and Betrixaban.	Venous thromboembolism [BD72]	[19]
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Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Carmellose sodium	E00625	Not Available	Disintegrant
Eisenoxyd	E00585	56841934	Colorant
Ferric hydroxide oxide yellow	E00539	23320441	Colorant
Magnesium stearate	E00208	11177	lubricant
Polyethylene glycol 3350	E00652	Not Available	Coating agent; Diluent; Ointment base; Plasticizing agent; Solvent; Suppository base; lubricant
Silicon dioxide	E00670	Not Available	Anticaking agent; Opacifying agent; Viscosity-controlling agent
Soybean lecithin	E00637	Not Available	Other agent
Talc	E00520	16211421	Anticaking agent; Diluent; Glidant; lubricant
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
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⏷ Show the Full List of 9 Pharmaceutical Excipients of This Drug

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Regorafenib 40 mg tablet	40 mg	Oral Tablet	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

1	Regorafenib FDA Label
2	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: 5891).
3	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
4	Stegeman BH, Vos HL, Helmerhorst FM, Rosendaal FR, Reitsma PH, van Hylckama Vlieg A: Genetic variation in the first-pass metabolism of ethinylestradiol, sex hormone binding globulin levels and venous thrombosis risk. Eur J Intern Med. 2017 Jul;42:54-60. doi: 10.1016/j.ejim.2017.05.019. Epub 2017 Jun 1.
5	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
6	Regorafenib is transported by the organic anion transporter 1B1 and the multidrug resistance protein 2. Biol Pharm Bull. 2015;38(4):582-6.
7	KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361. (dg:DG01913)
8	Brain and Testis Accumulation of Regorafenib is Restricted by Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1). Pharm Res. 2015 Jul;32(7):2205-16.
9	FDA Label of Regorafenib. The 2020 official website of the U.S. Food and Drug Administration.
10	Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138-148. doi: 10.1016/j.toxlet.2018.04.010. Epub 2018 Apr 12.
11	Regorefenib induces extrinsic/intrinsic apoptosis and inhibits MAPK/NF-B-modulated tumor progression in bladder cancer in vitro and in vivo. Environ Toxicol. 2019 Jun;34(6):679-688. doi: 10.1002/tox.22734. Epub 2019 Feb 25.
12	Cerner Multum, Inc. "Australian Product Information.".
13	Product Information. Stivarga (regorafenib). Bayer Pharmaceutical Inc, West Haven, CT.
14	Product Information. Sirturo (bedaquiline). Janssen Pharmaceuticals, Titusville, NJ.
15	Product Information. Turalio (pexidartinib). Daiichi Sankyo, Inc., Parsippany, NJ.
16	Product Information. Talzenna (talazoparib). Pfizer U.S. Pharmaceuticals Group, New York, NY.
17	Alderman CP, Moritz CK, Ben-Tovim DI "Abnormal platelet aggregation associated with fluoxetine therapy." Ann Pharmacother 26 (1992): 1517-9. [PMID: 1482806]
18	Patel S, Robinson R, Burk M "Hypertensive crisis associated with St. John's Wort." Am J Med 112 (2002): 507-8. [PMID: 11959071]
19	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
20	Product Information. Tivicay (dolutegravir). ViiV Healthcare, Research Triangle Park, NC.
21	Product Information. Orladeyo (berotralstat). BioCryst Pharmaceuticals Inc, Durham, NC.
22	Product Information. Movantik (naloxegol). Astra-Zeneca Pharmaceuticals, Wilmington, DE.
23	Product Information. Lorbrena (lorlatinib). Pfizer U.S. Pharmaceuticals Group, New York, NY.
24	Product Information. Retevmo (selpercatinib). Lilly, Eli and Company, Indianapolis, IN.
25	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]
26	Product Information. Zydelig (idelalisib). Gilead Sciences, Foster City, CA.
27	Product Information. Copiktra (duvelisib). Verastem, Inc., Needham, MA.
28	Product Information. Ubrelvy (ubrogepant). Allergan Inc, Irvine, CA.
29	Product Information. Nurtec ODT (rimegepant). Biohaven Pharmaceuticals, New Haven, CT.
30	Product Information. Xeglyze (abametapir topical). Dr. Reddy's Laboratories Inc, Upper Saddle River, NJ.
31	Product Information. Fycompa (perampanel). Eisai Inc, Teaneck, NJ.
32	Product Information. Tavalisse (fostamatinib). Rigel Pharmaceuticals, South San Francisco, CA.
33	EMA. European Medicines Agency. European Union "EMA - List of medicines under additional monitoring.".