sorafenib

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Ligands
sorafenib

GtoPdb Ligand ID: 5711

Synonyms: BAY 43-9006 | BAY-439006 | Nexavar®

sorafenib is an approved drug (FDA (2005), EMA (2006))

Comment: Sorafenib is a broad spectrum Type-2 kinase inhibitor targeting VEGFR2, VEGFR3, PDGFRβ, Flt3, and KIT and non-receptor kinases RAF1 and BRAF [8].

View interactive charts of activity data across species

View more information in the IUPHAR Pharmacology Education Project: sorafenib

sorafenib is commercially available from our sponsors

2D Structure

Physico-chemical Properties

Hydrogen bond acceptors	6
Hydrogen bond donors	3
Rotatable bonds	9
Topological polar surface area	92.35
Molecular weight	464.09
XLogP	3.75
No. Lipinski's rules broken	0

SMILES / InChI / InChIKey

Canonical SMILES	CNC(=O)c1nccc(c1)Oc1ccc(cc1)NC(=O)Nc1ccc(c(c1)C(F)(F)F)Cl
Isomeric SMILES	CNC(=O)c1nccc(c1)Oc1ccc(cc1)NC(=O)Nc1ccc(c(c1)C(F)(F)F)Cl
InChI	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)
InChI Key	MLDQJTXFUGDVEO-UHFFFAOYSA-N

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Summary of Clinical Use
Sorafenib was originally approved for treatment of approved for the treatment of advanced renal cell carcinoma, and further approved for advanced hepatocellular carcinoma. In November 2013, the FDA expanded the approval of sorafenib to allow it to be used to treat late-stage (metastatic) differentiated thyroid cancer. The clinically administered form is the sorafenib tosylate salt (PubChem CID 406563).

Summary of Clinical Use

Sorafenib was originally approved for treatment of approved for the treatment of advanced renal cell carcinoma, and further approved for advanced hepatocellular carcinoma. In November 2013, the FDA expanded the approval of sorafenib to allow it to be used to treat late-stage (metastatic) differentiated thyroid cancer. The clinically administered form is the sorafenib tosylate salt (PubChem CID 406563).

Mechanism Of Action and Pharmacodynamic Effects
Sorafenib is a multikinase inhibitor that decreases tumour cell proliferation in vitro. Sorafenib inhibits tumour growth of a broad spectrum of human tumour xenografts in athymic mice accompanied by a reduction of tumour angiogenesis. It is believed that sorfenib inhibits genetic transcription involved in cell proliferation and angiogenesis by targeting the Raf/Mek/Erk pathway. Specifically, sorafenib inhibits the activity of targets present in the tumour cell (CRAF, BRAF, V600E BRAF (VAR_018629), c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2, VEGFR-3, and PDGFR-β). RAF kinases are serine/threonine kinases, whereas c-KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-β are receptor tyrosine kinases.

Mechanism Of Action and Pharmacodynamic Effects

Sorafenib is a multikinase inhibitor that decreases tumour cell proliferation in vitro. Sorafenib inhibits tumour growth of a broad spectrum of human tumour xenografts in athymic mice accompanied by a reduction of tumour angiogenesis. It is believed that sorfenib inhibits genetic transcription involved in cell proliferation and angiogenesis by targeting the Raf/Mek/Erk pathway. Specifically, sorafenib inhibits the activity of targets present in the tumour cell (CRAF, BRAF, V600E BRAF (VAR_018629), c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2, VEGFR-3, and PDGFR-β). RAF kinases are serine/threonine kinases, whereas c-KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-β are receptor tyrosine kinases.

Pharmacokinetics
Absorption/Distribution
Following oral administration sorafenib reaches peak plasma concentrations in approximately 3 hours with a mean relative bioavailability of 38-49% for the tablet form, when compared to an oral solution. In vitro binding of sorafenib to human plasma proteins is 99.5 %.
Biotransformation/Metabolism
Metabolism occurs primarily in the liver by CYP3A4 and UGT1A9-mediated glucuronidation. The main circulating metabolite of sorafenib in plasma is the pyridine N-oxide which shows in vitro potency similar to that of sorafenib. At steady-state this metabolite comprises approximately 9-16% of circulating analytes.
Elimination
Elimination in the feces (77%) and urine (19%- as glucuronidated metabolites).
Population pharmacokinetics
Pharmacokinetics of sorafenib are not significantly affected by age or body weight. Total exposure is 30% lower in Asians than in white patients.
Organ function impairment
Mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic function impairment decreases exposure to sorafenib by 23% and 65%, respectively (not studied in subjects with severe hepatic function impairment). In clinical trials and clinical pharmacology studies no relationship is observed between sorafenib exposure and renal function in subjects with normal renal function, mild, moderate or severe renal impairment (no data is available in patients requiring dialysis).

Pharmacokinetics

Absorption/Distribution

Following oral administration sorafenib reaches peak plasma concentrations in approximately 3 hours with a mean relative bioavailability of 38-49% for the tablet form, when compared to an oral solution. In vitro binding of sorafenib to human plasma proteins is 99.5 %.

Biotransformation/Metabolism

Metabolism occurs primarily in the liver by CYP3A4 and UGT1A9-mediated glucuronidation. The main circulating metabolite of sorafenib in plasma is the pyridine N-oxide which shows in vitro potency similar to that of sorafenib. At steady-state this metabolite comprises approximately 9-16% of circulating analytes.

Elimination

Elimination in the feces (77%) and urine (19%- as glucuronidated metabolites).

Population pharmacokinetics

Pharmacokinetics of sorafenib are not significantly affected by age or body weight. Total exposure is 30% lower in Asians than in white patients.

Organ function impairment

Mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic function impairment decreases exposure to sorafenib by 23% and 65%, respectively (not studied in subjects with severe hepatic function impairment). In clinical trials and clinical pharmacology studies no relationship is observed between sorafenib exposure and renal function in subjects with normal renal function, mild, moderate or severe renal impairment (no data is available in patients requiring dialysis).