Sorafenib

Sorafenib

Clinical data
Other names	Nexavar Sorafenib tosylate
License data	EU EMA: by INN US FDA: Sorafenib
Pregnancy category	AU: D
Routes of administration	Oral
ATC code	L01XE05 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	29-49%
Protein binding	99.5%
Metabolism	Hepatic oxidation and glucuronidation (CYP3A4-mediated)
Elimination half-life	25–48 hours
Excretion	Fecal (77%) and renal (19%)
Identifiers
IUPAC name 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl-pyridine-2-carboxamide
CAS Number	284461-73-0
PubChem CID	216239
DrugBank	APRD01304
CompTox Dashboard (EPA)	DTXSID7041128
ECHA InfoCard	100.110.083
Chemical and physical data
Formula	C21H16ClF3N4O3
Molar mass	464.825 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES CNC(=O)C1=NC=CC(=C1)OC2=CC=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F

Sorafenib (marketed as Nexavar by Bayer), is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma).

Pharmacology

Sorafenib is a small molecular inhibitor of several Tyrosine protein kinases.

(Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous. These pathways include Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor. A growing number of drugs target most of these pathways.)

Sorafenib is unique in targeting the Raf/Mek/Erk pathway (MAP Kinase pathway).

Approval

Sorafenib was approved by the U.S. Food and Drug Administration (FDA) on December 20, 2005, and received a European Commission marketing authorization on July 19, 2006 (both for kidney cancer?).

The European Commission granted marketing authorization to Nexavar (sorafenib) tablets for the treatment of patients with hepatocellular carcinoma (HCC), the most common form of liver cancer, on October 30, 2007. .

Sorafenib obtained FDA approval for the treatment of advanced hepatocelluar carcinoma in November 2007.

Studies

Kidney

An article in The New England Journal of Medicine, published January 2007, showed compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed; the median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01). The first interim analysis of overall survival in May 2005 showed that sorafenib reduced the risk of death, as compared with placebo (hazard ratio, 0.72; 95% CI, 0.54 to 0.94; P=0.02), although this benefit was not statistically significant according to the O'Brien–Fleming threshold. Partial responses were reported as the best response in 10% of patients receiving sorafenib and in 2% of those receiving placebo (P<0.001).

Liver

At ASCO 2007, results from the SHARP trial were presented, which showed efficacy of sorafenib in hepatocellular carcinoma. The primary endpoint was overall survival, which showed a 44% improvement in patients who received sorafenib compared to placebo (hazard ratio 0.69; 95% CI, 0.55 to 0.87; p=0.0001). Both median survival and time to progression showed 3-month improvements. There was no difference in quality of life measures, possibly attributable to toxicity of sorafenib or symptoms related to underlying progression of liver disease. Of note, this trial only included patients with Child-Pugh Class A (ie mildest) cirrhosis. The results of the study appear in the July 24, 2008, edition of The New England Journal of Medicine. Because of this trial Sorafenib obtained FDA approval for the treatment of advanced hepatocelluar carcinoma in November 2007.

Lung

In some kinds of lung cancer (with squamous-cell histology) sorafenib administered in addition to paclitaxel and carboplatin may be detrimental to patients.

Thyroid cancer

A phase 3 clinical trial has started recruiting (Nov 2009) to use sorafenib for non-responsive thyroid cancer.

Adverse effects

Adverse effects of sorafenib include skin rash, hand-foot skin reactions, diarrhea, and hypertension. A case of diffuse yellow discoloration of the skin has been reported. Sorafenib has also been implicated in the development of reversible posterior leukoencephalopathy syndrome, yellow skin discoloration, reversible erythrocytosis.

References

7. Alexandrescu DT, McClure R, Farzanmehr H, Dasanu CA (August 2008). "Secondary erythrocytosis produced by the tyrosine kinase inhibitors sunitinib and sorafenib". Journal of Clinical Oncology 26(24):4047-8.

External links

• Nexavar.com – Manufacturer's website
• Prescribing Information – includes data from the key studies justifying the use of sorafenib for the treatment of kidney cancer (particularly clear cell renal cell carcinoma, which is associated with the von Hippel-Lindau gene)
• Patient Information from FDA
• Sorafenib in Treating Patients With Soft Tissue Sarcomas
• Clinical trial number NCT00217399 at ClinicalTrials.gov - Sorafenib and Anastrozole in Treating Postmenopausal Women With Metastatic Breast Cancer