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by Eve S. Shalom on behalf of the TRISTAN Consortium

EMIM 2024

Abstract

Improvement in the non-invasive assessment of hepatocellular function is needed for risk assessment of Drug-Drug Interactions (DDIs) and detection of Drug Induced Liver Injury (DILI) [1]. Many DDIs arise due to perpetrator drugs causing inhibition or induction of hepatic uptake or excretion of victim drugs, which can impact on their efficacy and toxicity. DILI can be caused by inhibited biliary excretion of a victim drug due to harmful accumulation within hepatocytes.

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) with Gadoxetate offers a potential avenue to probe risk assessment for DDIs and DILI [2], as Gadoxetate is a substrate for several hepatic transporters. TRISTAN Work Package 2 (WP2) focuses on the development of a standardised Gadoxetate DCE-MRI “biomarker” [3] including multi-centre phantom and animal studies to determine translatability of findings to humans.

Recent preclinical work from TRISTAN WP2 has focused on the assessment of sensitivity and reproducibility in identification of hepatocellular uptake and biliary excretion rates across multiple sites and field strengths, to deduce key points of variability. Rat subjects were assessed for the proposed biomarkers with and without six known liver inhibitors with the resulting values assessed. Issues in reproducibility were reported with significant differences between substudies for hepatocellular uptake and biliary excretion rates. However, hepatocellular uptake and biliary excretion rates were found to be above such detection limits for potent liver inhibitor drugs.

Within clinical settings, a study with healthy volunteers has been carried out by TRISTAN WP2 to assess sensitivity of the methodology with the effect of Rifampicin, a known liver inhibitor [4], on the derived hepatocellular biomarker values. The volunteers had DCE-MRI scans consisting of two investigations: (1) a baseline visit and (2) a follow up visit with Rifampicin administered prior scanning. The method reported a measurable and statistically significant reduction of both hepatocellular uptake and biliary excretion rates when Rifampicin was administered.

Both the preclinical and clinical work carried out in WP2 aim to contribute to evidence showing the potential benefit of biomarkers for hepatocyte uptake and biliary efflux for the risk assessment of DILI and DDI in both preclinical and clinical settings. This talk will cover details of these investigations which were undertaken as part of TRISTAN WP2 activities.