Development of a non-clinical platform for mechanistic studies of drug-induced cholestasis

This PhD project builds upon previous research at the laboratory in the domain of Drug-Induced Cholestasis (DIC), which is an important form of drug-induced liver injury. Liver injury as a consequence of drug-use negatively impacts the health of millions of patients worldwide. This phenomenon is also responsible for the failure of many drug-candidates in late clinical development phases. The laboratory of Pharmacotechnology and Biopharmacy has performed innovative research in this domain by using hepatocyte-based in vitro models for early DIC detection. More recently, also modeling-and simulation techniques were used to acquire quantitative insights in the underlying cellular mechanisms. The aim of this translational research is therefore to further integrate existing and improved in vitro and in silico models to establish a non-clinical platform to study DIC. Simultaneously mapping the kinetics of drugs (and their metabolites) and bile acids (as pivotal players in DIC) will be one of the most important characteristics and benefits of this platform. To summarize, this PhD project will include two important aspects: (i) in vitro laboratory research and, (ii) pharmacokinetic modeling. The in vitro part will mainly focus on accurately determining hepatobiliary dispositions of (potentially cholestasis-inducing) drugs (and metabolites), and on the disposition of the most important bile acid species. The in silico part consists of the iterative development of physiology-based pharmacokinetic models to predict in vivo cholestasis risk with the same drugs. Here, relevant (patho)physiologic information will be combined with drug-specific in vitro data.