Quantitative Systems Toxicology and Drug Development: The DILIsym Experience.

DILIsym® is a Quantitative Systems Toxicology (QST) model that has been developed over the last decade by a public-private partnership to predict the liver safety liability in new drug candidates. DILIsym integrates the quantitative abilities of parent and relevant metabolites to cause oxidative stress, mitochondrial dysfunction, and alter bile acid homeostasis. Like the prediction of drug-drug interactions, the data entered into DILIsym are assessed in the laboratory in human experimental systems, and combined with estimates of liver exposure to predict the outcome. DILIsym is now frequently used in decision-making within the pharmaceutical industry and its modeling results are increasingly included in regulatory communications and NDA submissions. DILIsym can be used to identify dominant mechanisms underlying liver toxicity and this information is increasingly being used to identify patient-specific risk factors, including certain disease states. DILIsym is also increasingly used to optimize the interpretation of liver injury biomarkers. DILIsym provides an example of how QST modeling can help speed the delivery of safer new drugs to the patients who need them.