Dr Dominic Williams

Associate Director

Preclinical Hepatic Safety

(AstraZeneca)

Dominic joined AstraZeneca in 2014 and is Associate Director within Drug Safety & Metabolism (DSM, Cambridge UK), the Preclinical Hepatic Target Organ Lead and co-Chair of the Hepatic Safety Knowledge Group.  

He sits on the AZ Post-Doc Committee which awards up to 50 post-doc positions each year, and has oversight of over 130 post-doc positions.

Until 2017, he was co-ordinator of the IMI1 consortium, MIP-DILI, and has been part of other EU initiatives (SAFE-T, SafeSciMET).  

Prior to joining AZ, Dominic has 15 years of academic experience in translational hepatic drug safety from within the UK’s only MRC funded Centre for Drug Safety Science, at the University of Liverpool and secured funding of over £10M.

Dominic led a research group and trained & developed 14 PhD and 6 Master’s students, some of whom are current employees of AstraZeneca.

Dominic has authored over 100 peer-reviewed publications on drug safety. Dominic sits on the Scientific & Nominations Sub-committees of the British Toxicology Society and has been a member of a Medicines & Healthcare Regulatory Agency (MHRA) Expert Advisory Group.

 

Novel Human-based Hepatic Safety Models for Mechanistic Risk Assessment: Deployment within the AstraZeneca hepatic safety toolbox

Abstract:

Drug-induced liver injury continues to be a major focus in candidate selection and clinical development in consideration of therapeutic index. Improved human cell based translational models, which recapitulate pathogenic mechanisms of liver toxicity, are required to assess hepatotoxicity risk to human.
An overview of hepatic adverse drug reaction and the pathogenesis and underlying mechanisms will be given. Pre-clinical hepatic safety questions that arise from projects and outline AstraZeneca’s hepatic safety assay toolbox will be discussed.
When and how AstraZeneca deploys particular assays for risk assessment vs hazard assessment will be described alongside assay validation and how we can move towards improved risk assessment through adoption of novel assays where we have confidence that correct hepatic safety mechanisms are appropriately represented.
Flow based Organs-Chip technology and 3D hepatic spheroid models represent promising models to assess mechanistic hepatotoxicity, due to enhanced cellular phenotype and stability whilst in culture. Evidence suggests these models demonstrate more in vivo-like injury mechanism representation and ability to report on drug-induced toxicity.
A comprehensive evaluation of an hepatic spheroid co-culture model and a Liver-Chip model will be outlined along with how this fits into an overall predictive model within AstraZeneca’s hepatic safety toolbox. Specifically, assessment of two model hepatotoxins for which metabolism is critical to their mechanisms of hepatotoxicity, acetaminophen (APAP) and
fialuridine (FIAU) have been assessed for sensitivity across a range of cytotoxicity biomarkers commonly employedin vitro(ATP, albumin, α-GST). Additionally, assessment of metabolic functionality by incorporating quantitation of APAP, FIAU and their principal metabolites has been evaluated.

Title Sponsor