Translating in vitro safety data into quantitative risk assessment in specific patient populations remains a challenge. This is especially true in the area of drug-induced liver injury. The DILI-sim Initiative is a ten year effort that has been supported by 19 of the largest pharmaceutical companies, the FDA, and academia. The Initiative has taken a “middle out” quantitative systems toxicology (QST) approach and uses differential equations to recapitulate key processes whereby drugs can cause liver injury. Simulated patient populations (SimPops) have been created by varying parameters to reflect genetic and non-genetic variation. The Initiative has produced software (DILIsym®, DILIsym Services Inc., a Simulations Plus Company) that is being increasingly employed in decision making within Pharma. To use the software, in vitro assays are performed on new drug candidates (and sometimes also on major metabolites) and these data are entered, along with estimates of liver exposure anticipated during a specified dosing regimen via GastroPlus®, into the software. The software then predicts the incidence and severity of liver injury anticipated in the target patient population. DILIsym has been tested in a validation cohort of drugs for which it has been reasonably accurate and very informative. Importantly, results from DILIsym have increasingly been included in regulatory submissions.
Dr. Paul B. Watkins will discuss key aspects of the clinical presentation of DILI, while Dr. Lisl K.M. Shoda will share recent published studies of DILIsym use focused on lixivaptan and PF-04895162.
Moderator:
Brett Howell
President
DILIsym Services, Inc
Panelists:
Paul Watkins
Director of the University of North Carolina Institute for Drug Safety Sciences,
Howard Q Ferguson Distinguished Professor of Pharmacy
Eshelman School of Pharmacy
Lisl Shoda
Principal Scientist
DILIsym Services, Inc