Sorafenib

Synonyms :
4-(4-((((4-Chloro-3-(trifluoromethyl)phenyl)amino)carbonyl)amino)phenoxy)-N-methyl-2-pyridinecarboxamide, N-(4-Chloro-3-(trifluoromethyl)phenyl)-n’-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, Sorafenibum

Status : approved

Category

Antineoplastic Agents

Therapeutic Classification

OTHER ANTINEOPLASTIC AGENTS

ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
OTHER ANTINEOPLASTIC AGENTS

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.

Used

Sorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma.

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.

Dosage

Form Route Strength
Tablet oral 200 mg
Tablet, film coated oral 200 mg

Pharmacodynamics

No large changes in QTc interval were observed. After one 28-day treatment cycle, the largest mean QTc interval change of 8.5 ms (upper bound of two-sided 90% confidence interval, 13.3 ms) was observed at 6 hours post-dose on day 1 of cycle 2.

Toxic Effect

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.

Metabolism

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.

Absorption

The mean relative bioavailability is 38-49% for the tablet form, when compared to an oral solution. Sorafenib reached peak plasma levels in 3 hours following oral administration. With a high-fat meal, bioavailability is reduced by 29% compared to administration in the fasted state.

Half Life

25-48 hours

Protein Binding

99.5% bound to plasma proteins.

Elimination Route

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.

Chemical Classification

This compound belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR’, where R and R’ are aryl groups.

Diarylethers

Organic compounds

Organooxygen compounds

Ethers

Diarylethers

Salt : Sorafenib Tosylate

Chemical Name

4-(4-((((4-Chloro-3-(trifluoromethyl)phenyl)amino)carbonyl)amino)phenoxy)-N-methyl-2-pyridinecarboxamide

Brands

name Dosage form Country
Nexavar tablet Canada
Nexavar tablet, film coated US

Drug Drug Interactions

  •  Acetaminophen  : May enhance the hepatotoxic effect of Sorafenib. Sorafenib may increase the serum concentration of Acetaminophen.
  •  Amodiaquine  : CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine.
  •  Atazanavir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Bevacizumab  : May enhance the adverse/toxic effect of Sorafenib. Specifically, the risk for hand-foot skin reaction may be increased.
  •  Boceprevir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Bosentan  : CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan.
  •  Bupropion  : CYP2B6 Inhibitors (Moderate) may increase the serum concentration of Bupropion.
  •  Butalbital  : Acetaminophen may enhance the hepatotoxic effect of Sorafenib. Sorafenib may increase the serum concentration of Acetaminophen.
  •  Carbamazepine  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Sorafenib.
  •  Carboplatin  : Sorafenib may enhance the adverse/toxic effect of Carboplatin.
  •  Carvedilol  : CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased.
  •  Ceritinib  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Cholic Acid  : BSEP/ABCB11 Inhibitors (Clinically Relevant) may decrease the excretion of Cholic Acid.
  •  Clarithromycin  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Clozapine  : Myelosuppressive Agents may enhance the adverse/toxic effect of Clozapine. Specifically, the risk for agranulocytosis may be increased.
  •  Cobicistat  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Dacarbazine  : SORAfenib may decrease the serum concentration of Dacarbazine. Sorafenib may also increase the concentration of dacarbazine’s active metabolite.
  •  Darunavir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Denosumab  : May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
  •  Docetaxel  : Sorafenib may increase the serum concentration of Docetaxel.
  •  Doxorubicin  : May increase the serum concentration of Doxorubicin (Conventional).
  •  Dronabinol  : CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol.
  •  Dronabinol  : CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol.
  •  Enzalutamide  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Sorafenib.
  •  Fluorouracil  : May decrease the serum concentration of Fluorouracil (Systemic). Sorafenib may increase the serum concentration of Fluorouracil (Systemic).
  •  Fosphenytoin  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Sorafenib.
  •  Idelalisib  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Indinavir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Irinotecan  : SORAfenib may increase the serum concentration of Irinotecan. Sorafenib may also increase the concentration of the active metabolite of irinotecan, SN-38.
  •  Isometheptene  : Acetaminophen may enhance the hepatotoxic effect of Sorafenib. Sorafenib may increase the serum concentration of Acetaminophen.
  •  Itraconazole  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Ketoconazole  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Leflunomide  : Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased.
  •  Metamizole  : May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased
  •  Mifepristone  : May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying).
  •  Mitotane  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Sorafenib.
  •  Natalizumab  : Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
  •  Nefazodone  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Nelfinavir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Neomycin  : May decrease the serum concentration of Sorafenib.
  •  Paclitaxel  : May enhance the adverse/toxic effect of Paclitaxel (Conventional).
  •  Phenobarbital  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Sorafenib.
  •  Phenytoin  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Sorafenib.
  •  Pimecrolimus  : May enhance the adverse/toxic effect of Immunosuppressants.
  •  Posaconazole  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Primidone  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Sorafenib.
  •  Rifabutin  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Sorafenib.
  •  Rifampicin  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Sorafenib.
  •  Rifapentine  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Sorafenib.
  •  Ritonavir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Roflumilast  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Saquinavir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Sipuleucel-T  : Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T.
  •  Telaprevir  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Telithromycin  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Tofacitinib  : Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib.
  •  Trastuzumab  : May enhance the neutropenic effect of Immunosuppressants.
  •  Voriconazole  : CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib.
  •  Warfarin  : Sorafenib may enhance the anticoagulant effect of Warfarin. Sorafenib may increase the serum concentration of Warfarin.

Calculated Property

kind Value Source
logP 4.12 ALOGPS
logS -5.4 ALOGPS
Water Solubility 1.71e-03 g/l ALOGPS
logP 4.34 ChemAxon
IUPAC Name 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide ChemAxon
Traditional IUPAC Name sorafenib ChemAxon
Molecular Weight 464.825 ChemAxon
Monoisotopic Weight 464.08630272 ChemAxon
SMILES CNC(=O)C1=NC=CC(OC2=CC=C(NC(=O)NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=C1 ChemAxon
Molecular Formula C21H16ClF3N4O3 ChemAxon
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) ChemAxon
InChIKey InChIKey=MLDQJTXFUGDVEO-UHFFFAOYSA-N ChemAxon
Polar Surface Area (PSA) 92.35 ChemAxon
Refractivity 114.52 ChemAxon
Polarizability 41.11 ChemAxon
Rotatable Bond Count 6 ChemAxon
H Bond Acceptor Count 3 ChemAxon
H Bond Donor Count 3 ChemAxon
pKa (strongest acidic) 11.55 ChemAxon
pKa (strongest basic) 2.03 ChemAxon
Physiological Charge 0 ChemAxon
Number of Rings 3 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 1 ChemAxon
Ghose Filter 1 ChemAxon
MDDR-Like Rule 1 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • Serine/threonine-protein kinase B-raf : in Human
  • RAF proto-oncogene serine/threonine-protein kinase : in Human
  • Vascular endothelial growth factor receptor 3 : in Human
  • Vascular endothelial growth factor receptor 2 : in Human
  • Receptor-type tyrosine-protein kinase FLT3 : in Human
  • Platelet-derived growth factor receptor beta : in Human
  • Mast/stem cell growth factor receptor Kit : in Human
  • Fibroblast growth factor receptor 1 : in Human
  • Proto-oncogene tyrosine-protein kinase receptor Ret : in Human
  • Vascular endothelial growth factor receptor 1 : in Human