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regorafenib 🐶 Veterinary Use | Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definition	Drug id	CAS RN
Raf (Rapidely Accelerated Fibrosarcoma) kinase inhibitors	4654	755037-03-7

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: regorafenib monohydrate Stivarga regorafenib regorafenib hydrate anhydrous regorafenib BAY 73-4506	Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl and CSF1R at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model and inhibition of tumor growth in several mouse xenograft models including some for human colorectal carcinoma, gastrointestinal stromal and hepatocellular carcinoma. Regorafenib also demonstrated anti-metastatic activity in a mouse xenograft model and two mouse orthotopic models of human colorectal carcinoma. Molecular weight: 482.82 Formula: C21H15ClF4N4O3 CLOGP: 4.88 LIPINSKI: 1 HAC: 7 HDO: 3 TPSA: 92.35 ALOGS: -5.67 ROTB: 6 Status: ONP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

regorafenib monohydrate
Stivarga
regorafenib
regorafenib hydrate
anhydrous regorafenib
BAY 73-4506

Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl and CSF1R at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model and inhibition of tumor growth in several mouse xenograft models including some for human colorectal carcinoma, gastrointestinal stromal and hepatocellular carcinoma. Regorafenib also demonstrated anti-metastatic activity in a mouse xenograft model and two mouse orthotopic models of human colorectal carcinoma.

Molecular weight: 482.82
Formula: C21H15ClF4N4O3
CLOGP: 4.88
LIPINSKI: 1
HAC: 7
HDO: 3
TPSA: 92.35
ALOGS: -5.67
ROTB: 6

Status: ONP

Legend:
OFP - off patent
OFM - off market
ONP - on patent

Drug dosage:

Dose	Unit	Route
0.12	g	O

ADMET properties:

None

Approvals:

Date	Agency	Company	Orphan
Aug. 26, 2013	EMA
Sept. 27, 2012	FDA	BAYER HLTHCARE

FDA Adverse Event Reporting System (Female)

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MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Palmar-plantar erythrodysaesthesia syndrome	1291.47	25.89	375	12111	22640	63453896
Dysphonia	432.37	25.89	203	12283	47411	63429125
Decreased appetite	252.19	25.89	277	12209	250775	63225761
Off label use	240.22	25.89	453	12033	674009	62802527
Metastases to lung	182.59	25.89	75	12411	12675	63463861
Fatigue	156.59	25.89	453	12033	887575	62588961
Diarrhoea	119.94	25.89	359	12127	715007	62761529
Hyperkeratosis	112.74	25.89	43	12443	5975	63470561
Asthenia	109.64	25.89	236	12250	383368	63093168
Blood bilirubin increased	109.51	25.89	76	12410	37064	63439472

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FDA Adverse Event Reporting System (Male)

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MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Palmar-plantar erythrodysaesthesia syndrome	2024.10	22.56	599	15527	16196	34924609
Dysphonia	707.69	22.56	299	15827	23084	34917721
Metastases to lung	356.01	22.56	141	15985	9179	34931626
Decreased appetite	335.36	22.56	397	15729	165995	34774810
Off label use	307.12	22.56	625	15501	418899	34521906
Fatigue	275.30	22.56	556	15570	370097	34570708
Metastases to liver	222.72	22.56	114	16012	13549	34927256
Diarrhoea	209.09	22.56	514	15612	389398	34551407
Blister	200.02	22.56	127	15999	22731	34918074
Hypertension	165.85	22.56	255	15871	136188	34804617

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FDA Adverse Event Reporting System (Geriatric)

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MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Palmar-plantar erythrodysaesthesia syndrome	3002.37	22.15	885	26232	32249	79685022
Dysphonia	1043.08	22.15	467	26650	56405	79660866
Decreased appetite	538.02	22.15	620	26497	341798	79375473
Metastases to lung	533.95	22.15	209	26908	17954	79699317
Off label use	487.54	22.15	995	26122	906220	78811051
Fatigue	361.98	22.15	898	26219	928829	78788442
Diarrhoea	308.59	22.15	818	26299	879671	78837600
Metastases to liver	305.37	22.15	162	26955	28152	79689119
Asthenia	233.32	22.15	527	26590	511162	79206109
Neuropathy peripheral	224.49	22.15	258	26859	141047	79576224

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FDA Adverse Event Reporting System (Pediatric)

None

Pharmacologic Action:

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Source	Code	Description
ATC	L01EX05	ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS ANTINEOPLASTIC AGENTS PROTEIN KINASE INHIBITORS Other protein kinase inhibitors
CHEBI has role	CHEBI:35610	antineoplastic agents
CHEBI has role	CHEBI:38637	tyrosine kinase inhibitors
CHEBI has role	CHEBI:50908	agente hepatotoxico
FDA EPC	N0000175605	Kinase Inhibitor
FDA MoA	N0000175076	Protein Kinase Inhibitors
FDA MoA	N0000185504	Cytochrome P450 2C9 Inhibitors

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Drug Use | Suggest Off label Use Form| |View source of the data|

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Disease	Relation	SNOMED_ID	DOID
Liver cell carcinoma	indication	109841003	DOID:684
Metastasis from malignant tumor of colon	indication	314998002
Gastrointestinal stromal tumor	indication	420120006	DOID:9253

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🐶 Veterinary Drug Use

None

🐶 Veterinary products

None

Acid dissociation constants calculated using MoKa v3.0.0

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Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	11.41	acidic
pKa2	11.83	acidic
pKa3	12.52	acidic
pKa4	2.76	Basic

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Orange Book patent data (new drug applications)

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Formulation strength	Trade name	Applicant	Application number	Approval date	Type	Dose form	Route	Patent number	Patent expiration date	Patent use
40MG	STIVARGA	BAYER HLTHCARE	N203085	Sept. 27, 2012	RX	TABLET	ORAL	8680124	June 2, 2030	TREATMENT OF PATIENTS WITH GASTROINTESTINAL STROMAL TUMOR (GIST), INCLUDING BUT NOT LIMITED TO PATIENTS PREVIOUSLY TREATED WITH IMATINIB AND PATIENTS WITH GIST HAVING RESISTANCE TO A KIT TYROSINE KINASE INHIBITOR

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Orange Book exclusivity data (new drug applications)

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Formulation strength	Trade name	Applicant	Application number	Approval date	Type	Dose form	Route	Exclusivity date	Description
40MG	STIVARGA	BAYER HLTHCARE	N203085	Sept. 27, 2012	RX	TABLET	ORAL	April 27, 2024	TREATMENT OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC OR LIVER CANCER) WHO HAVE BEEN PREVIOUSLY TREATED WITH THE DRUG SORAFENIB.

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Bioactivity Summary:

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Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
Vascular endothelial growth factor receptor 2	Kinase	P35968	VGFR2_HUMAN	INHIBITOR	IC50	7.90	IUPHAR	CHEMBL
Serine/threonine-protein kinase B-raf	Kinase	P15056	BRAF_HUMAN	INHIBITOR	IC50	7.55	CHEMBL	CHEMBL
Platelet-derived growth factor receptor beta	Kinase	P09619	PGFRB_HUMAN		IC50	8.82	CHEMBL
Tyrosine-protein kinase ABL1	Kinase	P00519	ABL1_HUMAN		Kd	6.12	CHEMBL
Mast/stem cell growth factor receptor Kit	Kinase	P10721	KIT_HUMAN		IC50	8.21	CHEMBL
Breakpoint cluster region protein	Kinase	P11274	BCR_HUMAN		Kd	6.13	CHEMBL
Ephrin type-A receptor 2	Kinase	P29317	EPHA2_HUMAN		Kd	6.08	CHEMBL
RAF proto-oncogene serine/threonine-protein kinase	Kinase	P04049	RAF1_HUMAN		IC50	8.82	CHEMBL
Receptor-type tyrosine-protein kinase FLT3	Kinase	P36888	FLT3_HUMAN		IC50	7.09	CHEMBL
Proto-oncogene tyrosine-protein kinase receptor Ret	Kinase	P07949	RET_HUMAN		Kd	6.90	CHEMBL

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External reference:

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ID	Source
014656	NDDF
1019206-88-2	SECONDARY_CAS_RN
11167602	PUBCHEM_CID
1312397	RXNORM
193440	MMSL
28887	MMSL
4031721	VANDF
5891	IUPHAR_LIGAND_ID
702804006	SNOMEDCT_US
703808002	SNOMEDCT_US

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Pharmaceutical products:

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Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
Stivarga	HUMAN PRESCRIPTION DRUG LABEL	1	50419-171	TABLET, FILM COATED	40 mg	ORAL	NDA	29 sections
Stivarga	HUMAN PRESCRIPTION DRUG LABEL	1	50419-171	TABLET, FILM COATED	40 mg	ORAL	NDA	29 sections

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