Mechanistic Modeling Aids in the Interpretation of Alanine Aminotransferase Elevations Associated with Clinical Ischemic Liver Injury

Authors: Church R, Aithal GP, Gulliver J, Hussaini H, Taneja G, Watkins PB
Conference: AASLD
Keywords: clinical ischemic liver injury, DILIsym, liver function, liver injury, mechanistic modeling
Software: DILIsym®
Division: Quantitative Systems Pharmacology (QSP)

Background

  • DILIsym® software can use serial serum alanine aminotransferase (ALT) assessments to predict hepatocyte loss (HL) and corresponding changes in total bilirubin (TBIL) due to reduction in global liver function as shown in Figure 1.
  • A mathematical equation, PALT, has been derived to estimate the maximum HL predicted by DILIsym without access to the software. PALT predicts a range of maximum hepatocyte loss (Figure 2) associated with the AUC and the peak value of an ALT kinetic profile.
  • DILIsym (and hence PALT) was optimized to estimates of HL (determined by biopsy) and peak serum TBIL levels observed in acetaminophen overdose
    patients2; therefore, it is unclear if the model of PALT accurately predicts HL and TBIL elevations in other liver injuries.
  • In this study we tested the ability of DILIsym to predict peak TBIL values associated with ischemic liver injury. Additionally, the maximum HL predicted by DILIsym was compared to PALT.

By RJ Church, GP Aithal, J Gulliver, H Hussaini, Guncha Taneja, Paul B Watkins

AASLD Liver Meeting, November 8-12, 2019, Boston, MA