For a workshop on predicting drug-induced cholestatic liver injury in humans.
Time & Location
Monday, March 12th, from 9:15 am to noon at the Henry B. Gonzalez Convention Center in San Antonio-Texas.
Drug-induced liver injury is a major reason of failure during premarketing and postmarketing phases of drug development. Being responsible for more than 50% of all cases of acute liver failure worldwide, drug-induced liver injury is equally of high clinical concern. As such, up to 40% of drug-induced liver injury patients present a cholestastic liver insult pattern. Cholestasis is derived from the Greek words chole and stasis meaning bile and halting, respectively, and denotes any situation of impaired bile secretion with concomitant accumulation of noxious bile acids in the liver or systemic circulation. Drug-induced cholestasis typically, though not uniquely, starts by inhibition of one or more drug transporters directly leading to bile acid retention in the liver. This triggers a deteriorative response associated with oxidative stress, inflammation and cell death. In parallel, an adaptive response is initiated, which is aimed at restricting bile acid synthesis and influx, while promoting bile acid efflux. In fact, these mechanisms have been embedded recently in an adverse outcome pathway construct in order to further facilitate predictive toxicology. Several additional key events in drug-induced cholestatic liver injury have been identified, including endoplasmic reticulum stress and mitochondrial impairment. Simultaneously, a number of human-based in silico (e.g. DILIsym®), ex vivo (e.g. precision-cut liver slices) an in vitro (e.g. sandwich cultures of human hepatocytes and 2-compartment systems) models have been introduced to mechanistically study drug-induced cholestatic injury. Such alternative animal-free models are cordially welcomed, not only because of ethical reasons, but also given the fact that preclinical animal models are not adequate predictors of human drug-induced liver injuries due to interspecies differences in bile acid profiles, transport and regulation. These non-animal methods, especially when combined, are able to accurately and quantitatively predict drug-induced cholestatic liver injury, thus emphasizing their overall clinical relevance.
9:15-9:20: Welcome/opening (Mathieu Vinken)
9:20-9:50: Mathieu Vinken
9:50-10:20: Kim Brouwer
10:20-10:50: Geny Groothuis
10:50-11:20: Kenneth Brouwer
10:20-11:50: Jim McKim
11:50-12:00: Wrap-up (Jim McKim)
For scheduling and appointments at SOT 2018 please contact Maryam Famourzadeh at firstname.lastname@example.org