SORAFENIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H16ClF3N4O3
Molecular Weight	464.825
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CNC(=O)C1=CC(OC2=CC=C(NC(=O)NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=CC=N1

InChI

InChIKey=MLDQJTXFUGDVEO-UHFFFAOYSA-N

InChI=1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31)

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021923s016lbl.pdf
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/20812347 https://www.ncbi.nlm.nih.gov/pubmed/16757355

Sorafenib (BAY 43-9006), marketed as Nexavar by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer, hepatocellular carcinoma and for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment. It has also received "Fast Track" designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer), and has since performed well in Phase III trials. Sorafenib was shown to interact with multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT- 3, VEGFR- 2, VEGFR- 3, and PDGFR- ß). Several of these kinases are thought to be involved in angiogenesis. Thus, sorafenib may inhibit tumor growth by a dual mechanism, acting either directly on the tumor (through inhibition of Raf and Kit signaling) and/or on tumor angiogenesis (through inhibition of VEGFR and PDGFR signaling). Sorafenib inhibited tumor growth of the murine renal cell carcinoma, RENCA, and several other human tumor xenografts in athymic mice. A reduction in tumor angiogenesis was seen in some tumor xenograft models.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase B-raf 20 Target ID: CHEMBL5145 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20812347	Inhibitor 8297
Serine/threonine-protein kinase RAF 10 Target ID: CHEMBL1906 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20812347	Inhibitor 8297
Vascular endothelial growth factor receptor 11 Target ID: CHEMBL2095227 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16757355	Inhibitor 8297
Tyrosine-protein kinase receptor FLT3 43 Target ID: CHEMBL1974 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17229632	Inhibitor 8297
Platelet-derived growth factor receptor beta 56 Target ID: CHEMBL1913 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17545544	Inhibitor 8297
Stem cell growth factor receptor 53 Target ID: CHEMBL1936 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17545544	Inhibitor 8297
Tyrosine-protein kinase receptor RET 14 Target ID: CHEMBL2041 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15466206	Inhibitor 8297	50.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Hepatocellular carcinoma 83 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021923s016lbl.pdf	Primary	Approved 8429	NEXAVAR Approved Use NEXAVAR is a kinase inhibitor indicated for the treatment of •Unresectable hepatocellular carcinoma (1.1) •Advanced renal cell carcinoma (1.2) •Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment (1.3) 1.1 Hepatocellular Carcinoma NEXAVAR® is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC). 1.2 Renal Cell Carcinoma NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 1.3 Differentiated Thyroid Carcinoma NEXAVAR is indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment. Launch Date 2005
Differentiated thyroid carcinoma 2 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021923s016lbl.pdf https://www.ncbi.nlm.nih.gov/books/NBK6979/	Primary	Approved 8429	NEXAVAR Approved Use NEXAVAR is a kinase inhibitor indicated for the treatment of •Unresectable hepatocellular carcinoma (1.1) •Advanced renal cell carcinoma (1.2) •Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment (1.3) 1.1 Hepatocellular Carcinoma NEXAVAR® is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC). 1.2 Renal Cell Carcinoma NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 1.3 Differentiated Thyroid Carcinoma NEXAVAR is indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment. Launch Date 2005
Renal cell carcinoma 31 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021923s016lbl.pdf	Primary	Approved 8429	NEXAVAR Approved Use NEXAVAR is a kinase inhibitor indicated for the treatment of •Unresectable hepatocellular carcinoma (1.1) •Advanced renal cell carcinoma (1.2) •Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment (1.3) 1.1 Hepatocellular Carcinoma NEXAVAR® is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC). 1.2 Renal Cell Carcinoma NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 1.3 Differentiated Thyroid Carcinoma NEXAVAR is indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment. Launch Date 2005

C_max

Value	Dose	Analyte	Population
0.43 mg/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/18477034	100 mg 2 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	SORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3.1 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22089297/	600 mg 2 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:	SORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3.8 μg/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652000/	400 mg 2 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:	SORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
9.4 mg × h/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/18477034	100 mg 2 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	SORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
12.6 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22089297/	600 mg 2 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:	SORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
17.9 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652000/	400 mg 2 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:	SORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
27.1 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/18477034	100 mg 2 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:		SORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.31% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22089297/	600 mg 2 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:		SORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.29% EXPERIMENT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652000/	400 mg 2 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:		SORAFENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
800 mg 2 times / day multiple, oral Highest studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21789159/ https://pubmed.ncbi.nlm.nih.gov/16061863/	unhealthy, Mean age 53.7 years n = 3 Health Status: unhealthy Condition: solid tumors Age Group: Mean age 53.7 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/21789159/ https://pubmed.ncbi.nlm.nih.gov/16061863/	DLT: Hypertension, Rash... Other AEs: Dyspnea, Rash... Dose limiting toxicities: Hypertension (grade 3, 33%) Rash (grade 2, 33%) Rash (grade 3, 67%) Other AEs: Dyspnea (grade 3, 33%) Rash (grade 3, 67%) Fatigue (grade 1, 67%) Anorexia (grade 1, 33%) Nausea (grade 1, 33%) Pharyngitis (grade 1, 33%) Dyspnea (grade 3, 33%) Pruritis (grade 1, 67%) Sources: https://pubmed.ncbi.nlm.nih.gov/21789159/ https://pubmed.ncbi.nlm.nih.gov/16061863/
600 mg 2 times / day multiple, oral MTD Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21789159/ https://pubmed.ncbi.nlm.nih.gov/16061863/	unhealthy, Mean age 53.7 years n = 6 Health Status: unhealthy Condition: solid tumors Age Group: Mean age 53.7 years Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21789159/ https://pubmed.ncbi.nlm.nih.gov/16061863/	Other AEs: Ascites, Constipation... Other AEs: Ascites (grade 3, 33%) Constipation (grade 3, 17%) Obstruction ureter (grade 3, 17%) Hypoalbuminemia (grade 3, 17%) Alkaline phosphatase (grade 3, 33%) Muscle weakness (grade 3, 17%) Depressed level of consciousness (grade 3, 17%) Pleural effusion (grade 3, 17%) Hypoxia (grade 3, 17%) Pruritis (grade 1, 17%) Rash (grade 1, 17%) Hypocalcemia (grade 1, 17%) Sources: https://pubmed.ncbi.nlm.nih.gov/21789159/ https://pubmed.ncbi.nlm.nih.gov/16061863/
800 mg 2 times / day multiple, oral Highest studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021923lbl.pdf https://pubmed.ncbi.nlm.nih.gov/21789159/ https://pubmed.ncbi.nlm.nih.gov/27981711/	unhealthy, Median age 57 years n = 20 Health Status: unhealthy Condition: metastatic renal cell carcinoma Age Group: Median age 57 years Sex: M+F Population Size: 20 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021923lbl.pdf https://pubmed.ncbi.nlm.nih.gov/21789159/ https://pubmed.ncbi.nlm.nih.gov/27981711/	Other AEs: Diarrhea... Other AEs: Diarrhea (22.5%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021923lbl.pdf https://pubmed.ncbi.nlm.nih.gov/21789159/ https://pubmed.ncbi.nlm.nih.gov/27981711/
800 mg 2 times / day multiple, oral Highest studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021923lbl.pdf https://pubmed.ncbi.nlm.nih.gov/27981711/	unhealthy, Median age 57 years n = 20 Health Status: unhealthy Condition: metastatic renal cell carcinoma Age Group: Median age 57 years Sex: M+F Population Size: 20 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021923lbl.pdf https://pubmed.ncbi.nlm.nih.gov/27981711/	Other AEs: Hand and foot skin reaction, Desquamation... Other AEs: Hand and foot skin reaction (10%) Desquamation (5%) Fatigue (12.5%) Hypertension (5%) Mucositis oral (2.5%) Alopecia (12.5%) Dry skin (12.5%) Nausea (12.5%) Vomiting (12.5%) Anorexia (15%) Weight loss (17.5%) Hypocalcaemia (12.5%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021923lbl.pdf https://pubmed.ncbi.nlm.nih.gov/27981711/
400 mg 2 times / day multiple, oral Recommended Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_MedR.pdf Page: 021923_s000_Nexavar_MedR.pdf - p.68-71	unhealthy, Median age 58 years n = 384 Health Status: unhealthy Condition: renal cell carcinoma Age Group: Median age 58 years Sex: M+F Population Size: 384 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_MedR.pdf Page: 021923_s000_Nexavar_MedR.pdf - p.68-71	Other AEs: Hypertension, Fatigue... Other AEs: Hypertension (grade 3, 2%) Fatigue (grade 3, 2%) Fever (grade 3, <1%) Weight loss (grade 3, <1%) Rash (grade 3, 1%) Hand and foot skin reaction (grade 3, 5%) Pruritus (grade 3, <1%) Flushing (grade 3, <1%) Diarrhea (grade 3, 2%) Nausea (grade 3, 1%) Anorexia (grade 3, 1%) Constipation (grade 3, 1%) Vomiting (grade 3, <1%) Mucositis (grade 3, <1%) Infection (grade 3, 1%) Cough (grade 3, <1%) Dyspnea (grade 3, 2%) Dyspnea (grade 4, <1%) Hypertension (grade 4, <1%) Fatigue (grade 4, <1%) Lymphopenia (grade 3, 5.1%) Amylase increased (grade 3, 2.4%) Hyperglycemia (grade 3, 4.1%) Hyperkalemia (grade 3, 2.1%) Lipase increased (grade 3, 3.5%) Hyponatremia (grade 3, 3.5%) Hypophosphatemia (grade 3, 1.8%) Lymphopenia (grade 4, 0.6%) Amylase increased (grade 4, 0.6%) Hyperglycemia (grade 4, 0.3%) Hyperkalemia (grade 4, 0.6%) Lipase increased (grade 4, 1.8%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_MedR.pdf Page: 021923_s000_Nexavar_MedR.pdf - p.68-71
100 mg 2 times / day multiple, oral Highest studied dose Dose: 100 mg, 2 times / day Route: oral Route: multiple Dose: 100 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15613696/	unhealthy, Median age 60 years n = 5 Health Status: unhealthy Condition: solid tumors Age Group: Median age 60 years Sex: M+F Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/15613696/	DLT: Diarrhea... Dose limiting toxicities: Diarrhea (grade 3, 20%) Sources: https://pubmed.ncbi.nlm.nih.gov/15613696/
400 mg 2 times / day multiple, oral MTD Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21789159/ https://pubmed.ncbi.nlm.nih.gov/15613696/	unhealthy, Median age 60 years n = 15 Health Status: unhealthy Condition: solid tumors Age Group: Median age 60 years Sex: M+F Population Size: 15 Sources: https://pubmed.ncbi.nlm.nih.gov/21789159/ https://pubmed.ncbi.nlm.nih.gov/15613696/	Disc. AE: Pancreatitis... AEs leading to discontinuation/dose reduction: Pancreatitis (grade 3, 6.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/21789159/ https://pubmed.ncbi.nlm.nih.gov/15613696/

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1478 CYP2B6 810 CYP2C8 911 UGT1A1 204 UGT1A9 116 CaV channel 4 P-gp 1461	UGT1A9 380 CYP2C8 693 UGT1A7 236 UGT1A1 418 UGT1A3 422 UGT1A4 347 UGT1A6 307 UGT1A8 283 UGT1A10 291 UGT2B4 249 UGT2B7 389 UGT2B15 203 UGT2B17 213 P-gp 1537	CYP1A2 701

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=6 Page: -	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=6 Page: -	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=47 Page: -	yes [IC50 0.84 uM]
UGT1A1 254	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=48 Page: -	yes [Ki 1.5 uM]
UGT1A9 121	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=48 Page: -	yes [Ki 1.5 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_MedR.pdf#page=45 Page: -	yes [Ki 17 uM]	no (co-administration study) Comment: Administration of NEXAVAR 400 mg twice daily for 28 days did not alter the exposure of concomitantly administered midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), or omeprazole (CYP2C19 substrate). Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_MedR.pdf#page=45 Page: -
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_MedR.pdf#page=45 Page: -	yes [Ki 2.4 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_MedR.pdf#page=45 Page: -	yes [Ki 4.2 uM]	no (co-administration study) Comment: Administration of NEXAVAR 400 mg twice daily for 28 days did not alter the exposure of concomitantly administered midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), or omeprazole (CYP2C19 substrate). Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_MedR.pdf#page=45 Page: -
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_MedR.pdf#page=45 Page: -	yes [Ki 4.9 uM]	no (co-administration study) Comment: Administration of NEXAVAR 400 mg twice daily for 28 days did not alter the exposure of concomitantly administered midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), or omeprazole (CYP2C19 substrate). Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_MedR.pdf#page=45 Page: -
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_MedR.pdf#page=45 Page: -	yes [Ki 6.2 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_MedR.pdf#page=45 Page: -	yes [Ki 7.3 uM]	no (co-administration study) Comment: The possible effect of sorafenib on a CYP2C9 substrate was assessed indirectly in patients receiving warfarin. The mean changes from baseline in PT-INR were not higher in NEXAVAR patients compared to placebo patients Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_MedR.pdf#page=45 Page: -
CaV channel 5	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_PharmR.pdf#page=32 Page: -	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=5 Page: -	major	no (co-administration study) Comment: Ketoconazole (400 mg), a potent inhibitor of CYP3 A4, administered once daily for 7 days did not alter the mean AUC of a single oral 50 mg dose of sorafenib in healthy volunteers. There is no clinical information on the effect of CYP3A4 inducers on the pharmacokinetics of sorafenib. Substances that are inducers of CYP3A4 activity are expected to increase metabolism of sorafenib and thus decrease sorafenib concentrations. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=5 Page: -
UGT1A1 418	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=28 Page: -	no
UGT1A10 291	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=28 Page: -	no
UGT1A3 422	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=28 Page: -	no
UGT1A4 347	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=28 Page: -	no
UGT1A6 307	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=28 Page: -	no
UGT1A8 283	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=28 Page: -	no
UGT2B15 203	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=28 Page: -	no
UGT2B17 213	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=28 Page: -	no
UGT2B4 249	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=28 Page: -	no
UGT2B7 389	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=28 Page: -	no
UGT1A9 380	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=5 Page: -	yes [Km 5.8 uM]
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=28 Page: -	yes
UGT1A7 236	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=28 Page: -	yes
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=47 Page: -	yes	unlikely Comment: The efflux ratio of sorafenib for transport from basolateral —> apical side to transport from the apical —> basolateral side of Caco-2 cells, ranged from 2.9 to 4.7. Given that sorafenib is highly permeable, the degree of efflux is not expected to result in an effect on overall absorption in man. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf#page=47 Page: -

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_PharmR.pdf#page=32 Page: -

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:50924	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:50924
ChemicalBook	CB42545752	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB42545752
MolPort	MolPort-003-850-270	https://www.molport.com/shop/molecule-link/MolPort-003-850-270
ZINC	ZINC000001493878	http://zinc15.docking.org/substances/ZINC000001493878
eMolecules	902486	https://www.emolecules.com/cgi-bin/more?vid=902486

PubMed

Title	Date	PubMed
Regulation of c-Raf-1: therapeutic implications.	2003 Aug	16258435
Novel agents for the treatment of advanced kidney cancer.	2004 Oct	16163253
Therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: biology, clinical results and future development.	2005 Aug	16042715
Recent progress in targeting the Raf/MEK/ERK pathway with inhibitors in cancer drug discovery.	2005 Aug	15955734
Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors.	2005 Aug 1	16061863
Subungual splinter hemorrhages: a clinical window to inhibition of vascular endothelial growth factor receptors?	2005 Aug 16	16103482
Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment.	2005 Dec	16474853
Sorafenib: scientific rationales for single-agent and combination therapy in clear-cell renal cell carcinoma.	2005 Dec	16425993
Role of tyrosine kinase inhibitors in cancer therapy.	2005 Dec	16002463
Gateways to clinical trials.	2005 Jun	16082422
Clinical trials referral resource.	2005 May	15971449
Gateways to clinical trials.	2005 Nov	16357953
Update on angiogenesis inhibitors.	2005 Nov	16224236
Targeted therapy in renal cell carcinoma.	2005 Oct	16185167
Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors.	2005 Oct	16006586
The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006.	2005 Oct 20	16007148
Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation.	2005 Oct 21	16109713
Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor Rapamycin.	2005 Oct 28	16255777
Results of a phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer.	2005 Sep	16197622
Spinal cord metastasis of a non-neurofibromatosis type-1 malignant peripheral nerve sheath tumor: an unusual manifestation of a rare tumor.	2005 Sep	16193390
Targeting multiple signal transduction pathways in lung cancer.	2005 Sep	16159418
Targeting angiogenesis with vascular endothelial growth factor receptor small-molecule inhibitors: novel agents with potential in lung cancer.	2005 Sep	16159417
Promising systemic therapy for renal cell carcinoma.	2005 Sep	16107239
Raf: a strategic target for therapeutic development against cancer.	2005 Sep 20	16170185
What's new in pancreatic cancer treatment pipeline?	2006 Apr	16549330
Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review.	2006 Aug	16418310
Drug approval triggers debate on future direction for cancer treatments.	2006 Feb	16521324
[Progress in therapeutic strategy for renal cell carcinoma].	2006 Feb	16484851
The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells.	2006 Feb 1	16452220
[Therapy strategies for advanced renal cell carcinoma].	2006 Jan	16372186
Second- and third-line treatments in non-small cell lung cancer.	2006 Jan	16343367
Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer.	2006 Jan 1	16397036
Raf-1 kinase associates with Hepatitis C virus NS5A and regulates viral replication.	2006 Jan 23	16405965
Targeting Raf-kinase: molecular rationales and translational issues.	2006 Jun	16760274
Emerging antiangiogenic agents in lung cancer.	2006 Mar	16640800
Molecule of the month. Sorafenib.	2006 Mar	16628266
VEGF-targeted therapy in renal cell carcinoma: active drugs and active choices.	2006 Mar	16507216
Sorafenib.	2006 Mar	16503817
Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome?	2006 Mar	16426838
BRAF is a therapeutic target in aggressive thyroid carcinoma.	2006 Mar 1	16533790
BAY 43-9006 inhibition of oncogenic RET mutants.	2006 Mar 1	16507829
Targeted therapy for metastatic renal cell carcinoma.	2006 Mar 13	16465192
Mechanisms of hypertension associated with BAY 43-9006.	2006 Mar 20	16446323
New drugs: abatacept, sorafenib, and nelarabine.	2006 Mar-Apr	16602235
Targeted therapy for cytokine-refractory metastatic renal cell carcinoma, and treatment in the community.	2006 May	16773842
Emerging efficacy endpoints for targeted therapies in advanced renal cell carcinoma.	2006 May	16773841
Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors.	2006 May	16500908
Pharmacodynamic monitoring of BAY 43-9006 (Sorafenib) in phase I clinical trials involving solid tumor and AML/MDS patients, using flow cytometry to monitor activation of the ERK pathway in peripheral blood cells.	2006 May	16498671
Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics.	2006 May	16133532
The place of VEGF inhibition in the current management of renal cell carcinoma.	2006 May 8	16508632

Patents

Sample Use Guides

In Vivo Use Guide

The recommended daily dose of NEXAVAR (tosylate salt of sorafenib) is 400 mg (2 x 200 mg tablets) taken twice daily, without food (at least 1 hour before or 2 hours after eating). Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. 432 433 434 435 436 437 438 439 Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of NEXAVAR therapy. When dose reduction is necessary, the NEXAVAR dose may be reduced to 400 mg once daily. If additional dose reduction is required, NEXAVAR may be reduced to a single 400 mg dose every other day

Route of Administration: Oral

In Vitro Use Guide

Patient-derived glioblastoma cells with low concentrations of sorafenib caused a dramatic dose dependent inhibition of proliferation (IC(50), 1.5 microM) and induction of apoptosis and autophagy. Sorafenib inhibited phosphorylation of signal transducer and activator of transcription 3 (Stat3) and expression of cyclins, D and E. In contrast, AKT was not modulated by sorafenib

Name

Type

Language

SORAFENIB

Official Name

English

SORAFENIB [USAN]

Common Name

English

SORAFENIB [MART.]

Common Name

English

SORAFENIB [EMA EPAR]

Common Name

English

2-PYRIDINECARBOXAMIDE, 4-(4-((((4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL)AMINO)CARBONYL)AMINO)PHENOXY)-N-METHYL-

Systematic Name

English

BAY 43-9006

Code

English

SORAFENIB [MI]

Common Name

English

4-(4-(3-(4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL)UREIDO)PHENOXY)-N(SUP 2)-METHYLPYRIDINE-2-CARBOXAMIDE

Systematic Name

English

Sorafenib [WHO-DD]

Common Name

English

SORAFENIB [VANDF]

Common Name

English

BAY-43-9006

Code

English

sorafenib [INN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C129825