Verkrijgen van mechanistisch inzicht in door geneesmiddelen veroorzaakte cholestase door middel van modellering en simulatie

Drug-induced liver injury (DILI) may impair liver function and lead to liver failure or even fatality, resulting in a considerable burden on the healthcare system. In addition, drug candidates that injure the liver may terminate clinical trials, be disapproved, or be withdrawn from the market, either of which causes appreciable losses for the pharmaceutical companies. To improve drug safety and minimise the attrition during drug development, developing approaches to detect the risk of DILI at an early stage is essential. As cholestasis typically associates with altered bile acid homeostasis, drug interactions that modulate the disposition of bile acids are considered a major underlying mechanism of DILI. Consistently, early detection of disturbed bile acid homeostasis may inform the potential of DILI caused by a drug (candidate). In silico modeling and simulation can translationally integrate the findings from in vitro, in vivo animal to clinical studies and allow the bottom-up prediction of in vivo risk. Therefore, the aim of this PhD project is (1) to develop a bottom-up Physiologically-based (pharmaco)kinetic (PB(P)K) modeling strategy for bile acids and drugs in special populations; (2) to deal with patients' variability in predicting the drug exposure; (3) to integrate mechanistic knowledge on DIC and PB(P)K modeling to predict in vivo DIC risk. Eventually, this PhD project is expected to inform drug safety at the early stage of drug development.