Pharma-validated DILI Prediction

• AstraZeneca and Genentech chose the validation compound set to be representative of a “real-world” situation. In order to conduct a truly independent assessment of the model, all 3D studies were performed at InSphero under conditions where the identities of the 110 compounds were blinded, and all 2D studies were conducted independently by Genentech.
• The compound set included some with limited solubility, as well as many weak DILI compounds with known rare and late DILI onset. For example, out of the 21 DILI compounds where no IC₅₀ value was determined, 14 compounds were only tested at less than 20-fold of the patients’ plasma concentrations due to solubility issues, thus preventing calculations of margin-of-safety.
• Four drugs (Stavudine, Methotrexate, Dantrolene, Nifedipine) were only toxic in vivo after several months of administration, and another drug (Trovafloxacin) is known to cause DILI in an idiosyncratic reaction, i.e., in the presence of inflammation, thus requiring different stimuli. Trovafloxacin toxicity was, however, correctly detected in the presence of an inflammatory stimulus.

Organotypic 3D InSight™ Human Liver Microtissues feature:

• Polarized hepatocytes with active hepatobiliary bile-salt secretion (BSEP and MRP2) and presence of bile canaliculi
• Preserved cytochrome P450 activity over the 14-day assay period
• 6-fold increase in mitochondrial spare respiratory capacity compared to 2D PHH
• Incorporation of inflammation-sensing Kupffer cells for detection of indirect effects on liver function

Displaying > 28-day in vitro longevity and more physiologically relevant biology, 3D InSight™ Human Liver Microtissues enable cumulative assessment of the most important factors driving DILI in vivo:

• Long-term drug exposure
• Active drug metabolism
• BSEP inhibition
• Mitochondrial impairment