Sorafenib

摘要: Sorafenib (Nexavar) is an orally active multikinase inhibitor that approved in the EU for treatment of hepatocellular carcinoma. Monotherapy with sorafenib prolongs overall survival and delays time to progression patients advanced carcinoma who are not candidates potentially curative or transarterial chemoembolization. generally well tolerated Thus, represents important advance new standard care this condition. The bi-aryl urea oral inhibits cell surface tyrosine kinase receptors (e.g. vascular endothelial growth factor platelet-derived receptor-beta) downstream intracellular serine/threonine kinases Raf-1, wild-type B-Raf mutant B-Raf); these involved tumour proliferation angiogenesis. In vitro, dose-dependent inhibition induction apoptosis was seen human cells lines. demonstrated antitumour activity a murine xenograft model Steady-state plasma concentrations were reached within 7 days advanced, refractory solid tumours received twice-daily sorafenib. Metabolism occurs primarily liver mediated via cytochrome P450 (CYP) 3A4 uridine diphosphate glucuronosyltransferase 1A9. carcinoma, differences pharmacokinetics between Child-Pugh A B considered clinically significant. may be associated drug interactions. For example, exposure reduced by average 37% concomitant administration CYP3A4 inducer rifampicin (rifampin); also decreased other inducers. 400 mg twice daily prolonged median delayed according results two randomized, double-blind, placebo-controlled, multicentre, phase III trials (the SHARP trial Asia-Pacific trial). There no significant difference placebo recipients symptomatic either trial. vast majority included A. Combination therapy plus doxorubicin did delay extent compared alone II However, durations progression-free significantly longer receiving than those alone. tegafur/uracil mitomycin showed potential noncomparative trials. manageable adverse effect profile; diarrhoea hand-foot skin reaction consistently most commonly occurring drug-related events clinical trial, any grade more diarrhoea, reaction, anorexia, alopecia, weight loss, dry skin, abdominal pain, voice changes 'other' dermatological events. similar tolerability profile As expected given addition chemotherapy agent, event combination differed somewhat monotherapy doxorubicin, all-cause (all grades) fatigue, neutropenia, elevated bilirubin levels, left ventricular dysfunction, hypertension febrile neutropenia.