regorafenib 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: 5.19 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: 5.19
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:

None

ADMET properties:

None

Approvals:

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

FDA Adverse Event Reporting System (Female)

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	1043.30	26.56	321	10441	20130	46655170
Dysphonia	384.53	26.56	184	10578	38230	46637070
Colorectal cancer metastatic	353.50	26.56	70	10692	650	46674650
Colorectal cancer	299.98	26.56	64	10698	883	46674417
Colon cancer	279.49	26.56	98	10664	9171	46666129
Decreased appetite	220.20	26.56	246	10516	193590	46481710
Off label use	173.10	26.56	311	10451	379530	46295770
Fatigue	161.47	26.56	399	10363	608298	46067002
Hepatocellular carcinoma	154.64	26.56	47	10715	2792	46672508
Blister	149.62	26.56	105	10657	44526	46630774
Metastases to lung	134.13	26.56	60	10702	10636	46664664
Skin exfoliation	97.75	26.56	72	10690	32866	46642434
Stomatitis	97.26	26.56	98	10664	68199	46607101
Hyperkeratosis	95.86	26.56	38	10724	4987	46670313
Pyrexia	95.33	26.56	232	10530	348570	46326730
Diarrhoea	91.46	26.56	309	10453	559293	46116007
Gastrointestinal stromal tumour	89.17	26.56	25	10737	1115	46674185
Carcinoembryonic antigen increased	88.30	26.56	26	10736	1383	46673917
Pain in extremity	84.82	26.56	185	10577	258495	46416805
Hypertension	84.12	26.56	157	10605	196199	46479101
Asthenia	83.94	26.56	206	10556	310869	46364431
Metastases to liver	82.16	26.56	53	10709	19532	46655768
Rectal cancer	81.16	26.56	26	10736	1836	46673464
Blood bilirubin increased	80.19	26.56	65	10697	34119	46641181
Rash	76.73	26.56	217	10545	356295	46319005
Oral pain	68.63	26.56	52	10710	24745	46650555
Weight decreased	63.63	26.56	146	10616	210703	46464597
Dehydration	62.62	26.56	123	10639	159417	46515883
Neuropathy peripheral	62.36	26.56	90	10672	90803	46584497
Blood pressure increased	57.57	26.56	104	10658	126562	46548738
Platelet count decreased	54.47	26.56	89	10673	99935	46575365
Dry skin	47.90	26.56	53	10709	40963	46634337
Hepatic function abnormal	44.61	26.56	47	10715	34374	46640926
Disseminated intravascular coagulation	44.25	26.56	36	10726	18969	46656331
Plantar erythema	41.08	26.56	10	10752	254	46675046
Colon cancer metastatic	41.00	26.56	14	10748	1206	46674094
Hospitalisation	40.89	26.56	61	10701	63324	46611976
Skin fissures	40.36	26.56	24	10738	7656	46667644
Mucosal inflammation	39.82	26.56	47	10715	38929	46636371
Condition aggravated	39.49	26.56	5	10757	245047	46430253
Gait inability	38.56	26.56	44	10718	35159	46640141
Tumour marker increased	38.51	26.56	18	10744	3523	46671777
Skin toxicity	37.97	26.56	18	10744	3636	46671664
Palmoplantar keratoderma	37.71	26.56	8	10754	107	46675193
Erythema	35.63	26.56	92	10670	142728	46532572
Drug ineffective	35.53	26.56	64	10698	677774	45997526
Abdominal pain	33.75	26.56	123	10639	229908	46445392
Hepatic encephalopathy	31.91	26.56	23	10739	10134	46665166
Dry mouth	30.03	26.56	49	10713	54877	46620423
Drug hypersensitivity	29.04	26.56	10	10752	243815	46431485
Drug interaction	28.57	26.56	6	10756	203088	46472212

FDA Adverse Event Reporting System (Male)

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	1756.95	23.13	527	13844	14343	29923764
Hepatocellular carcinoma	675.61	23.13	230	14141	9380	29928727
Dysphonia	638.95	23.13	265	14106	18767	29919340
Colorectal cancer	484.78	23.13	122	14249	1657	29936450
Colorectal cancer metastatic	445.29	23.13	102	14269	900	29937207
Colon cancer	309.26	23.13	125	14246	8247	29929860
Decreased appetite	306.10	23.13	367	14004	149543	29788564
Metastases to lung	295.48	23.13	119	14252	7776	29930331
Fatigue	240.22	23.13	494	13877	320179	29617928
Off label use	221.45	23.13	413	13958	248877	29689230
Blister	177.06	23.13	115	14256	20568	29917539
Metastases to liver	174.81	23.13	94	14277	11871	29926236
Diarrhoea	173.57	23.13	446	13925	333657	29604450
Gastrointestinal stromal tumour	160.96	23.13	48	14323	1258	29936849
Hypertension	142.46	23.13	228	14143	121126	29816981
Carcinoembryonic antigen increased	140.07	23.13	37	14334	613	29937494
Pain in extremity	127.82	23.13	206	14165	110015	29828092
Rectal cancer	117.98	23.13	43	14328	2133	29935974
Blood bilirubin increased	102.31	23.13	106	14265	36530	29901577
Skin exfoliation	101.25	23.13	86	14285	23086	29915021
Skin fissures	98.91	23.13	43	14328	3396	29934711
Asthenia	94.86	23.13	276	14095	221014	29717093
Dry skin	93.35	23.13	81	14290	22373	29915734
Weight decreased	87.75	23.13	211	14160	150710	29787397
Stomatitis	83.41	23.13	96	14275	37183	29900924
Hyperkeratosis	80.62	23.13	37	14334	3320	29934787
Blood pressure increased	74.59	23.13	128	14243	71800	29866307
Alpha 1 foetoprotein increased	74.08	23.13	23	14348	692	29937415
Ascites	72.89	23.13	88	14283	35833	29902274
Neuropathy peripheral	68.63	23.13	122	14249	70353	29867754
Hepatic function abnormal	60.65	23.13	87	14284	41858	29896249
Tumour marker increased	59.31	23.13	18	14353	501	29937606
Colon cancer metastatic	58.20	23.13	24	14347	1661	29936446
Oral pain	51.60	23.13	40	14331	9429	29928678
Hospitalisation	51.43	23.13	83	14288	44236	29893871
Toxicity to various agents	47.78	23.13	13	14358	177170	29760937
Abdominal pain upper	46.96	23.13	97	14274	62454	29875653
Hepatic encephalopathy	46.84	23.13	45	14326	14147	29923960
Aphonia	44.66	23.13	24	14347	3020	29935087
Metastases to lymph nodes	43.84	23.13	26	14345	3951	29934156
Dehydration	42.46	23.13	143	14228	123396	29814711
Glossodynia	42.44	23.13	24	14347	3337	29934770
Abdominal pain	40.58	23.13	150	14221	135504	29802603
Metastases to peritoneum	40.03	23.13	18	14353	1539	29936568
Drug interaction	38.72	23.13	24	14347	199544	29738563
Colorectal cancer recurrent	34.67	23.13	7	14364	31	29938076
Febrile neutropenia	34.63	23.13	5	14366	106688	29831419
Malaise	32.43	23.13	162	14209	166800	29771307
Acute kidney injury	32.35	23.13	51	14320	273791	29664316
Colon cancer recurrent	31.67	23.13	8	14363	110	29937997
Hypotension	31.42	23.13	30	14341	200535	29737572
Constipation	29.76	23.13	120	14251	112786	29825321
Cardiac arrest	28.67	23.13	5	14366	92845	29845262
Dry mouth	28.15	23.13	44	14327	22806	29915301
Overdose	27.25	23.13	4	14367	84333	29853774
Drug ineffective	27.19	23.13	79	14292	340308	29597799
Proteinuria	27.08	23.13	36	14335	16109	29921998
General physical health deterioration	26.96	23.13	107	14264	99837	29838270
Condition aggravated	26.13	23.13	17	14354	137849	29800258
Plantar erythema	26.07	23.13	6	14365	54	29938053
Rectal cancer metastatic	25.95	23.13	8	14363	235	29937872
Protein induced by vitamin K absence or antagonist II increased	25.81	23.13	5	14366	17	29938090
Skin toxicity	25.19	23.13	17	14354	3232	29934875
Metastases to adrenals	24.84	23.13	11	14360	907	29937200
Biliary obstruction	24.36	23.13	15	14356	2438	29935669
Rectal cancer stage IV	24.33	23.13	4	14367	3	29938104
Adverse drug reaction	23.69	23.13	41	14330	23104	29915003

Pharmacologic Action:

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

Drug Use (View source of the data)

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

Acid dissociation constants calculated using MoKa v3.0.0

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

Orange Book patent data (new drug applications)

None

Orange Book exclusivity data (new drug applications)

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.

Bioactivity Summary:

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
Bifunctional epoxide hydrolase 2	Enzyme	P34913	HYES_HUMAN	INHIBITOR	IC50	9.30	CHEMBL
Glycine receptor subunit alpha-1	Ion channel	P23415	GLRA1_HUMAN		EC50	5.74	CHEMBL

External reference:

ID	Source
D10137	KEGG_DRUG
1019206-88-2	SECONDARY_CAS_RN
4031721	VANDF
C2703114	UMLSCUI
CHEBI:68647	CHEBI
CHEMBL1946170	ChEMBL_ID
DB08896	DRUGBANK_ID
C559147	MESH_SUPPLEMENTAL_RECORD_UI
11167602	PUBCHEM_CID
5891	IUPHAR_LIGAND_ID
9026	INN_ID
24T2A1DOYB	UNII
1312397	RXNORM
193440	MMSL
28887	MMSL
d07913	MMSL
014656	NDDF
702804006	SNOMEDCT_US
703808002	SNOMEDCT_US

Pharmaceutical products:

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