Scientific background

Drug-induced liver injury (DILI) is among the most common ADRs, rendering the liver a priority target for drug safety studies [1]. Furthermore, liver toxicity has received particular attention as both European (EMA) and American (FDA) medical agencies have released regulatory guidelines to assess and interpret hepatotoxic signals in pre-clinical development [2]. As many hepatotoxicities only manifest rarely and only in specific patients, such side effects are often not seen until the drug has been on the market, sometimes for years, further increasing the withdrawal costs for the pharmaceutical industry. As a consequence, due to the proration of the expenses for these failed projects, the costs for each new chemical entity reaching marketing stage have been estimated at US$ 2.6 billion per new drug [3].

Thus, better tools are necessary for studying drug induced hepatotoxicity, and for understanding inter-individual differences in drug induced liver injury and liver diseases.

Cell lines and stem cell-derived hepatocytes have been discussed as potential models to detect drug-induced hepatotoxicity. Yet, hepatic cell lines exhibit very limited expression of most drug-metabolizing enzymes [4] and stem cell-derived hepatocytes retain fetal characteristics and do not present a relevant phenotype [5]. As a consequence, primary human hepatocytes (PHH) are considered the gold standard in vitro model system to study human drug-induced hepatotoxicity and liver diseases. However, when maintained in conventional 2D monolayer cultures, PHH dedifferentiate and lose hepatocyte-specific functions already after a few hours in culture,which significantly limits their utility for long-term functional studies. Thus, current cell culture systems do not provide a physiological setting for drug toxicity testing, which impairs the translatability of results obtained in vitro to man.

In the absence of relevant in vitro systems, animal models constitute a cornerstone to study liver pathobiology and to predict the effects of newly developed compounds in pre-clinical stages. Yet, the liver is an organ with pronounced species differences with regards to expression and catalytic activities of factors involved in drug absorption, distribution, metabolism and excretion (ADME). Thus, also animal models are endued with only limited predictive power of human in vivo pharmacokinetics.

 

References:

1. Cook et al., Nat Rev Drug Discov, 2014

2. Hughes, Nat Rev Drug Discov, 2008

3. http://csdd.tufts.edu/files/uploads/cost_study_backgrounder

4. Donato et al., Curr Drug Metab, 2013

5. Baxter et al., J Hepatol, 2015