Introduction

• Extensive progress has been made in identifying mechanisms for dose-dependent drug-induced liver injury (DILI) and in developing
  screening assays to reduce its incidence. However, idiosyncratic DILI (iDILI), or rare, often severe, adverse reactions that are not
  obviously dose-dependent, remain poorly predicted and extremely costly, both for patient health and for drug development companies.
• Some iDILI events appear immune-mediated based on delays between treatment initiation and DILI onset and more rapid injury upon
  drug re-challenge. Immune involvement has been further supported by the identification of HLA risk alleles for some drugs.
• DILIsym® software applies a quantitative systems toxicology (QST) approach to the understanding of dose-dependent DILI. It
  integrates in vitro mechanistic toxicity data, in vivo dynamic drug disposition, known biochemistry, and patient characteristics to predict
  the hepatotoxic potential of new drug candidates. Simulations can also provide a mechanistic rationale to account for liver signals
  observed in the clinic. [1]
• We seek to expand the scope of DILIsym (figure below, “Potential Adaptive Immune Addition to DILIsym”), utilizing an iDILI expansion
  framework laid out in [2], to reconcile clinical data implicating the immune response with mechanistic data characterizing liver-specific
  CD8+ T cell responses. The aim is to synthesize available data into a quantitative framework for hypothesis testing, further
  experimental design, and to increase knowledge of the preclinical/clinical potential to mitigate the occurrence of iDILI.

US FDA & AASLD DILI Conference at the University of Maryland University College May 7-8, 2019

By Zachary Kenz, Christina Battista, Lisl Shoda