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.
Antineoplastic Agents Immunosuppressive Agents Protein Kinase Inhibitors Antineoplastic and Immunomodulating Agents Cytochrome P-450 CYP1A2 Inhibitors Cytochrome P-450 CYP2C9 Inhibitors Cytochrome P-450 CYP1A2 Inducers Cytochrome P-450 CYP2C8 Inhibitors Cytochrome P-450 CYP2C9 Inducers Cytochrome P-450 CYP2C19 Inducers Cytochrome P-450 CYP2C8 Inducers Cytochrome P-450 CYP2B6 Inducers Cytochrome P-450 CYP2B6 Inhibitors CYP2B6 Inhibitors (strong) CYP2D6 Inducers CYP2D6 Inducers (strong) CYP3A4 Inhibitors Combined Inhibitors of CYP3A4 and P-glycoprotein
Sorafenib 200 MG
Sorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma.
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.
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.
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.
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.
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.
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.
Low white blood cell count or low platelet count. Feeling tired or weak. High blood pressure. Upset stomach or throwing up. Many small meals, good mouth care, sucking hard, sugar-free candy, or chewing sugar-free gum may help. Loose stools (diarrhea). Hair loss. Hair most often grows back when this drug is stopped. Not hungry. Bleeding problems. Itching. Weight loss. Belly pain. Muscle pain. Rash. Heart disease may rarely happen. Holes in the GI (gastrointestinal) tract may rarely happen.