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 are thought to be immune-mediated, based on delayed onset and rapid re-injury after resuming drug. 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 now seek to expand the scope of DILIsym to reconcile clinical data implicating the immune response with mechanistic data characterizing liver-specific CD8+ T cell responses.
• Incorporation of CD8+ T cell mediated hepatocyte death in DILIsym is designed 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.

Ninth American Conference on Pharmacometrics (ACoP) Annual Meeting, October 6-12, 2018, San Diego, CA

By Zackary Kenz, Christina Battista, Lisl Shoda