Sorafenib

Absorption

The administration of multiple doses for seven days resulted in a 2.5- to 7-fold accumulation compared to a single dose. Steady-state concentrations were achieved within seven days, with a peak-to-trough ratio of mean concentrations of less than 2. 
The mean relative bioavailability was 38–49% following the administration of oral sorafenib tablets. A high-fat meal reduced bioavailability by 29%.

Toxicity

The oral lowest published toxic dose (Toxic Dose Low, TDLo) is 2.84 mg/kg/21D (intermittent). The oral LD50 of sorafenib tosylate in rats is >2000 mg/kg.
The adverse reactions observed at 800 mg sorafenib twice daily (twice the recommended dose) were primarily diarrhea and dermatologic. 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. The prescribing information recommends the discontinuation of sorafenib treatment and initiation of supportive care in cases of suspected overdose.

Description

Sorafenib is a small molecular inhibitor of several kinases involved in tumor angiogenesis and proliferation, including, but not limited to, Raf (IC₅₀=12nM for Raf-1), VEGFR (IC₅₀=90nM for VEGFR-2 and IC₅₀=12nM for VEGFR-3), and platelet derived growth factor receptor (IC₅₀=57nM for PDGFR-b). Specifically, sorafenib blocks tumor progression by inhibiting cellular proliferation that is dependent on activation of the MAPK pathway (Raf) and/or inhibiting tumor angiogenesis through VEGFR and/or PDGFR. While it may be effective in the treatment of a variety of tumors, the first approvable indication is for renal cell carcinoma. Overall, the drug appears to be well tolerated by the majority of patients at the 400 mg b.i.d. continuous dosing. As an inhibitor of multiple kinases vital for tumor progression, sorafenib may possess wide-spectrum antitumor properties and may emerge as an effective weapon against a variety of solid tumors.

Chemical properties

Light Yellow Solid

Originator

Bayer/Onyx (Germany)

Characteristics

Class: receptor tyrosine kinase
Treatment: RCC, HCC, thyroid cancer
Elimination half-life = 25–48 h
Protein binding = 99.7%

Characteristics

The complex of sorafenib with a nonphosphorylated VEGFR2 construct comprising the catalytic and juxtamembrane (JM) domain shows the activation loop adopts a DFG-out position. The net effect of sorafenib’s interactions with the kinase is to stabilize the DFG motif in an inactive conformation. The lipophilic trifluoromethyl phenyl ring at the opposite end of the molecule inserts into a hydrophobic pocket formed between the -C and -E helices and amino-terminal regions of the DFG motif and catalytic loop. The urea functionality forms two crucial hydrogen bonds, one with the backbone aspartate of the DFG loop and the other with the glutamate side chain of the -C helix. In the auto-inhibited state, the DFG-out segment, particularly Phe1047, blocks ATP-binding. When the JM rearranges out of the regulatory domain pocket (RDP), then the DFG is unlocked and able to switch to the open activated state. Autophosphorylation, which activates the kinase presumably through stabilization of an active conformation, was shown to occur on the JM and then the DFG-containing activation loop sequentially. Sorafenib fills the binding channel, making an important H-bond to Asp1046, two H-bonds to the side chain carboxylate oxygen of Glu885, and two H-bonds to Cys919. The selectivity of sorafenib derives from the formation of these four hydrogen bonds and attractive van der Waals (dispersion) interactions.

The Uses of Sorafenib

A potent RAF kinase inhibitor. Antineoplastic

The Uses of Sorafenib

Multiple kinase inhibitor targeting both RAF kinase and receptor tyrosine kinases that promote angiogensis. Antineoplastic.

The Uses of Sorafenib

Sorafenib Tosylate (Bay 43-9006, Nexavar) is a small molecular inhibitor of VEGFR, PDGFR, c-Raf and B-Raf with IC50s of 18 nM, 10 nM, 3 nM and 15 nM, respectively.

Background

Sorafenib is a bi-aryl urea and an oral multikinase inhibitor. It targets cell surface tyrosine kinase receptors and downstream intracellular kinases that are implicated in tumour cell proliferation and tumour angiogenesis. First approved by the FDA and European Commission in 2007 for the treatment of hepatocellular carcinoma, sorafenib is also indicated to treat renal carcinoma and differentiated thyroid carcinoma.

Indications

Sorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma.
In the US, it is also indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma that is refractory to radioactive iodine treatment.

Indications

Sorafenib (Nexavar(R), Bayer) was the first approved inhibitor targeting the vascular endothelial growth factor (VEGF) family kinases, which include VEGFR1, VEGR2, and VEGFR3. Sorafenib was originally approved for the treatment of renal cell carcinoma (RCC) in 2005, hepatocellular carcinoma in 2007, and locally recurrent or metastatic thyroid carcinoma refractory to radioactive iodine treatment in 2013. Six other approved inhibitors with VEGFRs as the main targets are sunitinib (Sutent(R), Pfizer) for RCC, soft tissue sarcoma, thyroid cancer,metastatic pancreatic tumors, gastrointestinal stromal tumor, and several other types of carcinomas; pazopanib (Votrient(R), GlaxoSmithKline) for RCC, soft tissue sarcoma, and thyroid cancer; axitinib (Inlyta(R), Pfizer) for RCC,thyroid cancer, and aplastic anemia, as well as T315I-mutant Bcr–Abl1-driven leukemia; regorafenib (Stivarga(R), Bayer) for gastrointestinal stromal tumors and colorectal cancer; nintedanib (Ofev(R), Boehringer Ingelheim) for the non-oncological indication of idiopathic pulmonary fibrosis; and lenvatinib (Lenvima(R), Eisai Inc.) for RCC and different types of thyroid cancers. Sunitinib, pazopanib, and lenvatinib bind to the “DFG-in”conformation of VEGFRs, while axitinib, regorafenib, and nintedanib bind to inactive VEGFRs adopting the “DFG-out”conformation.

Definition

 ChEBI: Sorafenib is a member of the class of phenylureas that is urea in which one of the nitrogens is substituted by a 4-chloro-3-trifluorophenyl group while the other is substituted by a phenyl group which, in turn, is substituted at the para position by a [2-(methylcarbamoyl)pyridin-4-yl]oxy group. It has a role as an antineoplastic agent, an EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor, a tyrosine kinase inhibitor, an angiogenesis inhibitor, an anticoronaviral agent and a ferroptosis inducer. It is a pyridinecarboxamide, a member of monochlorobenzenes, an aromatic ether, a member of (trifluoromethyl)benzenes and a member of phenylureas.

brand name

Nexavar (Bayer HealthCare); Xarelto (Bayer HealthCare).

Flammability and Explosibility

Non flammable

Pharmacokinetics

Sorafenib decreases tumour cell proliferation in vitro. It attenuated tumour growth of human tumour xenografts in immunocompromised mice, reduced tumour angiogenesis, and increased tumour apoptosis in models of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma. Some studies suggest that sorafenib induces apoptosis in several tumour cell lines, although this effect is inconsistent across cell lines. 

Clinical Use

Protein kinase inhibitor:
Treatment of advanced renal cell carcinoma
Treatment of hepatocellular carcinoma
Treatment of thyroid cancer

Synthesis

An improved, four-step synthesis in 63% overall yield was published recently and is illustrated in the scheme. Picolinic acid (127) was heated with Vilsmeier reagent for 16 hr to give 128 in 89% yield as an off-white solid. The acid chloride 128 was treated with methylamine in methanol at low temperature to give amide 129 in 88% yield as paleyellow crystals after its crystallization from ethyl acetate.
4-Aminophenol anion was generated under a basic condition and compound 129 was added to the anion solution to give corresponding addition compound 131 in 87% yield. For an unknown reason, potassium carbonate used in the reaction increased the reaction rate significantly. Finally, compound 131 was condensed with isocyanate 132 in methylene chloride to give sorafenib (XVIII) in 92% yield as a white solid.

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: may enhance effect of coumarins.
Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).
Antivirals: avoid with boceprevir.

Metabolism

Sorafenib undergoes oxidative metabolism by CYP3A4 in the liver, as well as glucuronidation by UGT1A9 in the liver and kidneys. At steady-state, sorafenib accounts for 70-85% of the circulating analytes in plasma. About eight metabolites of sorafenib have been identified, of which five were detected in plasma.

Metabolism

Sorafenib is metabolised primarily in the liver and undergoes oxidative metabolism mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. 8 metabolites have been identified, during in vitro studies one has been shown to have equal activity to sorafenib. About 96% of a dose is excreted within 14 days, with 77%, mostly as unchanged drug, recovered in the faeces, and 19% in the urine as glucuronidated metabolites.

storage

Store at -20°C