Chairperson(s): Monicah Otieno, Janssen Pharmaceuticals, Spring House, PA; and Paul Watkins, The Hamner-UNC Institute for Drug Safety Sciences, Research Triangle Park, NC.
Drug Discovery Toxicology Specialty Section
Mechanisms Specialty Section
Drug-induced liver injury (DILI) in the clinic is a major cause for drug attrition during development. DILI can be characterized as intrinsic or idiosyncratic. Properties of intrinsic DILI include a dose-response in presentation of injury that may be predicted by animal studies enabling application of safety thresholds and inclusion of liver injury biomarkers for clinical risk assessment. Idiosyncratic DILI (iDILI) is unpredictable and usually occurs following drug exposure in large populations e.g., during Phase III clinical trials or postmarketing. Given that this is a major cause for costly drug withdrawals, there has been significant effort in identifying properties that predispose some compounds to a high risk for iDILI. Both immune and nonimmune mechanisms are hypothesized to contribute to iDILI. This course will discuss DILI hazards that can be used to identify
a compound’s potential to cause DILI. A general overview and introduction of DILI will be provided, followed by a clinician’s perspective on DILI focusing on presentation of DILI using examples of key withdrawals. Subsequent presentations will focus on established and emerging science on DILI hazard risks; this will include a presentation on the role of reactive metabolites (RM) and covalent binding in increasing risk for immune or nonimmune mediated DILI. A basic overview on mechanisms of RM formation, methods for detection, and mechanistic studies correlating covalent binding with DILI will be discussed. The relationship between dose, covalent binding thresholds, and DILI also will be addressed. This will be followed by a presentation on hepatic transporters and the role
they play in DILI, either through delayed hepatotoxicity resulting from liver accumulation of parent/metabolites and/or inhibition of efflux of toxic bile acids. Mitochondrial toxicity also has been identified as a key hazard for DILI compounds; an overview of mitochondrial toxicity, its role in iDILI, and how interplay with hepatic transport inhibition may increase risk for DILI will be presented. The final presentation will introduce the concept of computational, systems pharmacology approaches integrating all of the mechanisms discussed by the previous speakers along with drug exposure, to put data from various sources into context.