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May 7, 2019
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Development of a Direct CD8+ T Cell Activation QSP Model for Ovalbumin in the Context of Liver Injury Advances Groundwork for Mathematical Representation of Idiosyncratic Drug-Induced Liver Injury (iDILI)

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

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