Klinische en preklinische evaluatie van de behandeling van hepatocellulair carcinoom: focus op farmacokinetiek

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, causing a significant health challenge globally, taking the lives of nearly a million people every year. The incidence of HCC is projected to increase by over 50% by 2040, and the primary risk factors are chronic infections with hepatitis B and C viruses (HBV and HCV) and alcohol-related liver diseases; however, non-alcoholic fatty liver disease (NAFLD), which is linked to metabolic syndrome, is also becoming the main risk of HCC, especially in Western countries. The highest incidence of HCC is reported in developing regions like East Asia, the Middle East, and Sub-Saharan Africa, where the highest burden of HBV and HCV infections is. Inadequate surveillance and limited treatment options are the main challenges in these regions, and the disease is usually diagnosed at an advanced stage, leading to poor patient prognoses. Moreover, the HBV vaccination coverage is too low in low- and middle-income countries. Given the differences in etiological factors and HCC treatment approaches across various regions, it is imperative to generate country-specific data to develop more effective clinical management strategies, highlighting the significance of our clinical study conducted in Ethiopia. Furthermore, sorafenib and lenvatinib, both tyrosine kinase inhibitors (TKIs), remain a primary class of systemic therapies for patients with advanced HCC. However, they are associated with the risk of serious adverse effects, such as hepatotoxicity, which can significantly affect the clinical outcome. For instance, about 25% of HCC patients treated with sorafenib experience elevated aminotransferase levels linked to liver injury. Yet, the underlying mechanisms of liver toxicity are not well understood, highlighting the importance of our study. One potential mechanism is the disruption of bile acid (BA) synthesis and transport, which may lead to cholestatic liver injury. This highlights the importance of studying the effects of sorafenib and lenvatinib on major efflux transporters involved in bile acid transport.