Drug/Small Molecule:
sorafenib

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2D structure

Overview

Generic Names
  • Sorafenib tosylate
  • sorafenib
Trade Names
  • Nexavar
Brand Mixture Names

PharmGKB Accession Id:
PA7000

Description

Sorafenib (rINN), marketed as Nexavar by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer). 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 is a small molecular inhibitor of Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 & 3 kinases and c Kit the receptor for Stem cell factor. A growing number of drugs target most of these pathways. The originality of Sorafenib lays in its simultaneous targeting of the Raf/Mek/Erk pathway.

Source: Drug Bank

Indication

For the treatment of patients with advanced renal cell carcinoma.

Source: Drug Bank

ATC Therapeutic Category

  • L01XE:Protein kinase inhibitors

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Sorafenib interacts 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 reduces blood flow to the tumor. Sorafenib is unique in targeting the Raf/Mek/Erk pathway. By inhibiting these kinases, genetic transcription involving cell proliferation and angiogenesis is inhibited.

Source: Drug Bank

Pharmacology

Sorafenib is a multikinase inhibitor targeting several serine/threonine and receptor tyrosine kinases. It is commonly available as a tosylate salt. Sorafenib is a multikinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib inhibits tumor growth of the murine renal cell carcinoma, RENCA, and several other human tumor xenografts in athymic mice. A reduction in tumor angiogenesis occurs in some tumor xenograft models.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady- state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady-state.

Source: Drug Bank

Protein Binding

99.5%

Source: Drug Bank

Absorption

The mean relative bioavailability is 38-49% for the tablet form, when compared to an oral solution. With a high-fat meal, bioavailability is reduced by 29% compared to administration in the fasted state.

Source: Drug Bank

Half-Life

25-48 hours

Source: Drug Bank

Toxicity

The highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhea and dermatologic events. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals.

Source: Drug Bank

Route of Elimination

Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted in urine as glucuronidated metabolites.

Source: Drug Bank

Chemical Properties

Chemical Formula

C21H16ClF3N4O3

Source: Drug Bank

Isomeric SMILES

CNC(=O)c1cc(ccn1)Oc2ccc(cc2)NC(=O)Nc3ccc(c(c3)C(F)(F)F)Cl

Source: OpenEye

Canonical SMILES

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

Source: Drug Bank

Average Molecular Weight

464.825

Source: Drug Bank

Monoisotopic Molecular Weight

464.08630272

Source: Drug Bank

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

  1. VEGF Signaling Pathway
    Model endothelial cell displaying genes of the VEGF signalling pathway and the sites at which bevacizumab, sorafenib, sunitinib, brivanib and cilengitide are known to act.

External Pathways

Links to non-PharmGKB pathways.

PharmGKB contains no links to external pathways for this drug. To report a pathway, click here.

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

EvidenceGene
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
KDR
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
MAPK1
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
MAPK10
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
MAPK11
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
MAPK12
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
MAPK13
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
MAPK14
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
MAPK3
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
MAPK4
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
MAPK6
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
MAPK7
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
MAPK8
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
MAPK9
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
RAF1

Drug Targets

Gene Description
BRAF (source: Drug Bank)
BRAF (source: Drug Bank)
FLT3 (source: Drug Bank)
FLT3 (source: Drug Bank)
FLT4 (source: Drug Bank)
FLT4 (source: Drug Bank)
KDR (source: Drug Bank)
KDR (source: Drug Bank)
KIT (source: Drug Bank)
KIT (source: Drug Bank)
PDGFRB (source: Drug Bank)
PDGFRB (source: Drug Bank)
RAF1 (source: Drug Bank)
RAF1 (source: Drug Bank)
No related drugs are available.
No related diseases are available

Publications related to sorafenib: 13

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Two drug interaction studies of sirolimus in combination with sorafenib or sunitinib in patients with advanced malignancies. Clinical cancer research : an official journal of the American Association for Cancer Research. 2011. Gangadhar Tara C, et al. [Article:21447721@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Efficacy and safety of sorafenib in a subset of patients with advanced soft tissue sarcoma from a Phase II randomized discontinuation trial. Investigational new drugs. 2011. Pacey Simon, et al. [Article:20016927@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension. Clinical pharmacology and therapeutics. 2010. Gomberg-Maitland M, et al. [Article:20010555@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Targeted cancer therapies in the twenty-first century: lessons from imatinib. Clinical pharmacology and therapeutics. 2010. Stegmeier F, et al. [Article:20237469@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs. Oncogene. 2010. Ramakrishnan V, et al. [Article:19935717@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available PW
Vascular endothelial growth factor pathway. Pharmacogenetics and genomics. 2010. Maitland Michael L, et al. [Article:20124951@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics. 2010. Beaulieu Mathieu, et al. [Article:21121811@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment. Clinical cancer research : an official journal of the American Association for Cancer Research. 2009. Maitland Michael L, et al. [Article:19773379@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs. 2009. Keating Gillian M, et al. [Article:19228077@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A phase II clinical trial of sorafenib in androgen-independent prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008. Dahut William L, et al. [Article:18172272@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Results from an in vitro and a clinical/pharmacological phase I study with the combination irinotecan and sorafenib. European journal of cancer (Oxford, England : 1990). 2007. Mross K, et al. [Article:17095207@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Sorafenib in advanced clear-cell renal-cell carcinoma. The New England journal of medicine. 2007. Escudier Bernard, et al. [Article:17215530@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer research. 2004. Wilhelm Scott M, et al. [Article:15466206@PubMed]

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
50419-488-58
DrugBank:
DB00398
PDB:
BAX
ChEBI:
50924
PubChem Compound:
216239
PubChem Substance:
46505329
789424
BindingDB:
16673
ChemSpider:
187440
HET:
BAX
Therapeutic Targets Database:
DAP000006

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Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.
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