regorafenib + ketoconazole

Regorafenib is an orally administered small molecule multikinase inhibitor used primarily for the treatment of metastatic colorectal cancer, unresectable or metastatic gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma. It inhibits multiple membrane-bound and intracellular kinases involved in oncogenesis (such as RET, KIT, BRAF), tumor angiogenesis (VEGFR1/2/3, TIE2), and the tumor microenvironment (PDGFR-alpha/beta, FGFR1/2). Regorafenib is developed by Bayer and marketed under the brand name Stivarga[2][5][6]. Ketoconazole is an imidazole antifungal agent used to treat a variety of fungal infections. It acts by inhibiting ergosterol synthesis through inhibition of fungal cytochrome P450 enzymes. Ketoconazole also strongly inhibits human CYP3A4 enzyme activity and can significantly increase plasma concentrations of drugs metabolized by this pathway[4][8]. The combination "regorafenib + ketoconazole" refers to co-administration rather than a fixed-dose combination product. This pairing is clinically significant because ketoconazole's potent CYP3A4 inhibition can markedly increase exposure to regorafenib—raising risk for toxicity.