DILIsym

DILIsym® is the flagship quantitative systems toxicology (QST) software platform developed by Simulations Plus for predicting and explaining drug-induced liver injury (DILI). Designed to support safety assessment throughout the drug development process, DILIsym helps organizations evaluate the potential liver safety hazard posed by individual molecules and gain deeper mechanistic insight into observed DILI responses. It is the most widely used QST modeling software for DILI prediction and serves as a recognized source of QST modeling-based data assessed by the FDA's DILI team.

DILIsym development is supported by the DILI-sim Initiative, a pre-competitive consortium comprising Simulations Plus and multiple pharmaceutical companies. Member companies contribute directly to directing development efforts and provide ongoing feedback to the DILIsym development team, ensuring the platform evolves in line with industry needs.

Core Modeling Modules

• PBPK Modeling: Physiologically based pharmacokinetic modeling to characterize compound disposition in the liver.
• Mitochondrial Toxicity Modeling: Assessment of mitochondrial dysfunction as a mechanism of hepatotoxicity.
• Bile Acid Modeling: Simulation of bile acid transporter inhibition and its downstream effects.
• Reactive Nitrogen/Oxygen Species: Modeling of oxidative and nitrosative stress pathways.
• Innate Immunity Modeling: Representation of immune-mediated contributions to liver injury.
• Hepatocyte Life Cycle: Simulation of hepatocyte proliferation, necrosis, and regeneration dynamics.
• Clinical Readouts: Prediction of clinically relevant biomarkers including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, prothrombin time, and INR.
• SimPops®: Simulated human populations that express a wide range of responses to compounds, characterized by extensive variability in underlying biochemistry.

Species-Specific Physiological Representations

• DILIsym Humans: A middle-out multi-scale representation of human physiology integrating compound pharmacokinetic (PK) and pharmacodynamic (PD) information to predict time profiles of liver enzymes and other clinical variables, as well as tissue properties such as liver mass and GSH content. Supports investigation of alternate mechanistic hypotheses including increased reactive oxygen/nitrogen species, ATP utilization, direct hepatocyte necrosis, and inhibition of bile acid transporters.
• DILIsym Dogs: A middle-out multi-scale representation of Beagle dog physiology for assessing potential DILI hazard in preclinical dog studies, with datasets prioritized from Beagle dogs for maximum consistency.
• DILIsym Rats: A middle-out multi-scale representation of Sprague-Dawley rat physiology, enabling prediction of time profiles of liver enzymes and tissue properties from integrated PK/PD data.
• DILIsym Mice: A middle-out multi-scale representation of C57Bl/6 mouse physiology for assessing DILI hazard in mouse models, with datasets prioritized from C57Bl/6 mice.

Key Capabilities and Applications

• Simulated Population Testing (SimPops®): Test compounds across simulated populations to capture inter-individual variability in biochemical responses and identify susceptible subpopulations.
• Mechanistic Hypothesis Investigation: Explore and differentiate between multiple downstream mechanisms of drug action to understand the drivers of observed liver injury.
• Translational Research: Integrate in vitro, small animal, and large animal compound data into a single platform to facilitate cross-species translation and better inform program advancement decisions, including experimental design, analyte selection, and sampling timing.
• Clinical Biomarker Prediction: Generate time-course predictions of liver enzyme elevations and other clinical variables relevant to regulatory and clinical decision-making.
• Regulatory Support: Provides QST modeling-based data recognized by the FDA's DILI team, supporting regulatory submissions and safety assessments.

DILIsym is available for licensing and evaluation, and a free introductory tutorial comprising 12 modules is available for Version 11. The platform is backed by a team of expert quantitative systems pharmacology scientists at Simulations Plus and has been applied by leading pharmaceutical companies including Biohaven and Astellas, with findings supported by an extensive body of peer-reviewed publications.