Combining sorafenib and immunosuppression in liver transplant recipients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) recurrence after liver transplantation occurs in approxi-mately 20% of patients. Most of these patients use immunosuppressant drugs. Meanwhile, patients with HCC recurrence are frequently treated with the small molecule kinase inhibitor (SMKI) so-rafenib. However, sorafenib and many immunosuppressants are substrates of the same enzymatic pathways (e.g., CYP3A4), which may potentially result in altered SMKI or immunosuppressant plasma levels. Therefore, we investigated changes in drug exposure of both sorafenib and immuno-suppressants over time in four patients with systemic immunosuppressant and sorafenib treatment after HCC recurrence. In this study, sorafenib exposure declined over time during combined treatment with immunosuppressants, while two patients also experienced declining tacrolimus plasma levels. Importantly, patients were unable to increase the sorafenib dose higher than 200 mg b.i.d. without experiencing significant toxicity. We recommend to treat patients using both sorafenib and immunosuppressants with a sorafenib starting dose of 200 mg b.i.d.