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

Stem definitionDrug idCAS RN
Raf (Rapidely Accelerated Fibrosarcoma) kinase inhibitors 4654 755037-03-7

Description:

MoleculeDescription

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:

DateAgencyCompanyOrphan
Aug. 26, 2013 EMA
Sept. 27, 2012 FDA BAYER HLTHCARE

FDA Adverse Event Reporting System (Female)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients 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 termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients 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:

SourceCodeDescription
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)

DiseaseRelationSNOMED_IDDOID
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 levelDissociation constantType (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 strengthTrade nameApplicantApplication numberApproval dateTypeDose formRouteExclusivity dateDescription
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:

TargetClassPharosUniProtActionTypeActivity value
(-log[M])
Mechanism
action
Bioact sourceMoA source
Vascular endothelial growth factor receptor 2 Kinase INHIBITOR IC50 7.90 IUPHAR CHEMBL
Serine/threonine-protein kinase B-raf Kinase INHIBITOR IC50 7.55 CHEMBL CHEMBL
Bifunctional epoxide hydrolase 2 Enzyme INHIBITOR IC50 9.30 CHEMBL
Glycine receptor subunit alpha-1 Ion channel EC50 5.74 CHEMBL

External reference:

IDSource
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:

ProductCategoryIngredientsNDCFormQuantityRouteMarketingLabel
Stivarga HUMAN PRESCRIPTION DRUG LABEL 1 50419-171 TABLET, FILM COATED 40 mg ORAL NDA 29 sections