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DILIsym®

Liver ModelThe DILIsym® modeling software is designed to be used during drug development to provide an enhanced understanding of the Drug Induced Liver Injury (DILI) hazard posed by individual molecules and to provide deeper insight into the mechanisms responsible for observed DILI responses at various stages of the development process. DILIsym® software allows users to carry out in vitro to in vivo extrapolation, translate preclinical results to clinical trial protocol design, and to evaluate the impact of patient variability on predicted hepatotoxicity. Simulations provide a better understanding of how in vitro assay results relate to DILI responses in animals and people.


  • DILIsym Model

    DILIsym Overview

    Systems Pharmacology Modeling
  • DILIsym® is a “middle-out”, multi‑scale representation of drug-induced liver injury. It includes key liver cell populations (e.g., hepatocytes, Kupffer cells), intracellular biochemical systems (e.g., mitochondrial dysfunction), and whole body dynamics (e.g., drug distribution and metabolism). The model represents physiological data for mice, rats, dogs, and humans. Through the generation of SimPops™ (alternate parameterizations of the model with distribution constraints), the DILIsym® software also includes inter‑individual variability.

    By integrating preclinical data, DILIsym® allows you to predict hepatotoxicity for small preclinical species (i.e., in vitro to in vivo extrapolation, IVIVE, for mice or rats), large preclinical species (i.e., in vitro and rodent data to dog predictions), first-in-human clinical trials, and phase II/III clinical trials.

    DILIsym® is built in the MATLAB computing platform (The MathWorks, Natick, MA). Users may work directly with the MATLAB code or may use a graphical user interface (GUI). The GUI permits the specification of new experiments, including compound, dose, dosing frequency, duration, mechanism(s), and species. Simulations can be performed on individuals or populations. Simulation results can be visualized within MATLAB or can be exported for further analysis using other software.

    DILIsym® prospectively supports key management decisions by providing information on experimental or clinical designs that would uncover liver toxicity, as well as mechanistic rationale for the underlying biochemical events that would cause liver toxicity. The model retrospectively supports key management decisions by mechanistically interpreting data to distinguish innocuous vs. dangerous liver signals.

SUB-MODELS

Mitochondrial toxicity modeling

The representation of mitochondrial biochemistry within the model scope includes mitochondrial respiration, proton-motive force, and ATP production in addition to compounds that disrupt these processes. Exemplar compounds have been simulated to refine the model and ensure that the modeled representation of mitochondrial toxicity is consistent with available data. The exemplar compounds include tolcapone, entacapone, CP-724714, buprenorphine, and etomoxir. The model also incorporates associated pathways that participate in the overall hepatic response to mitochondria toxicity in vivo (e.g., glycolysis). Further, a separate standalone model of in vitro mitochondrial respiration and ATP production (MITOsym®) has been constructed and provides direct comparisons with in vitro mitochondrial assays to support parameter identification.

Innate immunity modeling

The representation of the innate immune response within the model scope includes macrophage (Kupffer) and liver sinusoidal endothelial cell (LSEC) populations. Macrophages and immunomodulatory molecules produced by macrophages have been shown to modify the course of APAP hepatotoxicity in animal models and are also present in human APAP overdose. LSECs regulate immune cell recruitment to the liver and produce molecules that are involved in the regeneration phase of hepatotoxicity. APAP serves as the primary exemplar compound as most of the available data characterizes the role of these cells and molecules in APAP hepatotoxicity. These include liposomal clodronate (for macrophage depletion), a HMGB1 antagonist, and a TNF-a antagonist.

Bile acid modeling

The representation of bile acid biochemistry within the model scope includes the dynamics of specific bile acids implicated in hepatotoxicity. The model incorporates bile acid synthesis, uptake, recirculation, and efflux, including key transporters (e.g., bile salt efflux pump or BSEP). Drug-induced changes to bile acid dynamics can increase intracellular bile acids with subsequent hepatotoxicity. Exemplar compounds have been simulated to refine the model and ensure that the modeled representation of bile acid toxicity is consistent with available data. The exemplar compounds include bosentan, troglitazone, pioglitazone, telmisartan, glibenclamide, CP-724714, and AMG009.

 

Functions

DILIsym® modeling software functions include:

  • General population samples: The DILIsym® software can be used to test compounds in simulated populations, termed SimPops™. Simulated individuals within the SimPops™ express a wide range of response to the various exemplar compounds and can be characterized by extensive variability in their underlying biochemistry.
  • DILIsym® humans: A middle-out multi-scale representation of human physiology for assessing potential DILI hazard in patients. Compound pharmacokinetic (PK) and pharmacotoxicologic (PT) information can be integrated to predict time profiles of liver enzymes (i.e., alanine aminotransferase, aspartate aminotransferase) and other clinical variables (e.g., bilirubin, prothrombin time, INR), as well as tissue properties (e.g., liver mass, GSH content). Alternate hypotheses regarding the downstream mechanisms of drug action can be investigated, 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 dogs. Data from Beagle dogs were prioritized among the available datasets to maximize consistency in the representation.
  • DILIsym® rats: A middle-out multi-scale representation of Sprague-Dawley rat physiology for assessing potential DILI hazard in rats. Data from Sprague-Dawley rats were prioritized among the available datasets to maximize consistency in the representation. Compound pharmacokinetic and pharmacotoxicologic information can be integrated to predict time profiles as described above.
  • DILIsym® mice: A middle-out multi-scale representation of C57Bl/6 mouse physiology for assessing potential DILI hazard in mice. Data from C57Bl/6 mice were prioritized among the available datasets to maximize consistency in the representation. Compound pharmacokinetic and pharmacotoxicologic information can be integrated to predict time profiles as described above.
  • Translational research: The ability to integrate your in vitro, small animal, and large animal compound data into a single platform facilitates translational research to better inform program advancement decisions, including experimental design, analyte selection, and timing of sampling.

Key features of the DILIsym® modeling software

  • In vitro extrapolation to in vivo predictions (IVIVE) of DILI hazard in multiple preclinical species and in humans
  • Predicted DILI hazard can be traced back to its mechanistic source(s)
  • Incorporates inter-individual physiological variability
  • Incorporates PK and pharmacotoxicologic variability
  • User-friendly GUI to specify in silico experiments and visualize results
  • Transparent design and parameterization
  • Inclusive incorporation of the available literature for mechanistic representation of the physiology
  • Regularly updated to include leading edge science
  • Developed and supported by scientific and technical teams
  • Informs drug development decisions and risk mitigation strategies