Pharmacokinetic boosting approach for tyrosine kinase inhibitors – Sorafenib and Lenvatinib – targeting hepatocellular carcinoma

Lenvatinib and sorafenib are the only FDA- and EMA-approved tyrosine kinase inhibitors (TKIs) indicated for hepatocellular carcinoma (HCC). Despite having such molecular-targeted medications, the overall observed survival of HCC patients is still modest. We assume that a major challenge in achieving high therapeutic efficacy is inadequate intracellular concentration of TKIs. Because the target sites are inside the cell, the intracellular bioavailability of HCC-targeted lenvatinib and sorafenib is key for their optimal anticancer activities, suggesting the clinical implications of determining intrahepatic concentrations of lenvatinib and sorafenib. The cellular uptakes of many TKIs including lenvatinib and sorafenib are mainly mediated by the organic anion transporting polypeptides (OATP1B1/3), while the breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) have been found to be their major efflux pathways. Studies, however, showed that the expression and activities of major uptake transporters OATPs are markedly downregulated; whereas, efflux pumps like BCRP and P-gp are slightly upregulated in the liver tumor. These imply less drug is reached and accumulated inside the tumor, which may justify a reduced cytotoxic effect of anticancer agents, like the TKIs. Hence, activating the downregulated OATP isoforms and/or altering the activities of efflux pumps in cancer cells are assumed to be suitable approaches to enhance intracellular drug accumulation. This PhD project, therefore, primarily aims to explore possible pharmacokinetic (PK) boosting agents/strategies that increase the intrahepatic concentrations of lenvatinib and sorafenib, and subsequently enhance their clinical efficacy. When feasible, the effects of most promising PK boosting agents will further be tested and verified in animal models, in vivo. Basically, the LC-MS/MS methods will be developed and validated to analyse samples of lenvatinib and sorafenib from in vitro assays and in vivo animal studies. A physiologically based pharmacokinetic (PBPK) model will eventually be developed to describe the intracellular exposure profiles of lenvatinib and sorafenib in HCC patients.