Session 4: Drug-induced hepatocyte
Cyprotex Discovery Ltd.
ABSTRACT CONTENT / DETAILS:
Drug induced liver injury (DILI) is a major cause of late stage attrition in drug development. Although hepatic steatosis (fatty accumulation of the liver) is regarded as a relatively mild effect, it may lead to more serious DILI and may be indicative of serious underlying causes such as the inhibition of mitochondrial respiration.
The aim of our study was to predict in vivo steatosis in rodents and humans from in vitro high-content screening (HCS) data and estimated in vivo pharmacokinetics (PK), by constructing a phenomenological model of cellular triglyceride response to drug challenge. Fitting the model to the HCS data for individual drugs generated parameters for each drug. These were used with estimated in vivo plasma concentrations to drive in vivo steatotic response, and compared with in vivo observations.
Steatosis in mouse, rat and human on exposure to tetracycline was modelled using HCS triglyceride accumulation data from HepG2 cells. The model was also used to predict triglyceride accumulation on exposure to cyclosporin A and tamoxifen.
Using this model, in vitro HCS data and physiologically-based phamacokinetic (PBPK) modelling could be used to predict the steatotic potential of drug candidates, or be used to aid optimization of dosing regimens to minimise steatosis of existing drugs whilst maintaining efficacy.