title: The role of quantitative systems pharmacology modeling in the prediction and explanation of idiosyncratic drug-induced liver injury.
abstract: Idiosyncratic drug-induced liver injury (iDILI) is a serious concern in drug development. The rarity and multifactorial nature of iDILI makes it difficult to predict and explain. Recently, human leukocyte antigen (HLA) allele associations have provided strong support for a role of an adaptive immune response in the pathogenesis of many iDILI cases; however, it is likely that an adaptive immune attack requires several preceding events. Quantitative systems pharmacology (QSP), an in silico modeling technique that leverages known physiology and the results of in vitro experiments in order to make predictions about how drugs affect biological processes, is proposed as a potentially useful tool for predicting and explaining critical events that likely precede immune-mediated iDILI, as well as the immune attack itself. DILIsym, a QSP platform for drug-induced liver injury, has demonstrated success in predicting the presence of delayed hepatocellular stress events that likely precede the iDILI cascade, and has successfully predicted hepatocellular stress likely underlying iDILI attributed to troglitazone and tolvaptan. The incorporation of a model of the adaptive immune system into DILIsym would represent and important advance. In summary, QSP methods can play a key role in the future prediction and understanding of both immune-mediated and non-immune-mediated iDILI.
authors.affiliation: DILIsym Services, Inc., 6 Davis Drive, Research Triangle Park, NC 27709, USA. Electronic address: jwoodhead@dilisym.com.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Woodhead
authors.affiliation: Institute for Drug Safety Sciences, UNC-Eshelman School of Pharmacy, 6 Davis Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
authors.affiliation: DILIsym Services, Inc., 6 Davis Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Howell
authors.affiliation: DILIsym Services, Inc., 6 Davis Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Scott Q
authors.initials: SQ
authors.lastname: Siler
authors.affiliation: DILIsym Services, Inc., 6 Davis Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Lisl K M
authors.initials: LKM
authors.lastname: Shoda
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology; D002839:Chromans / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008954:Models, Biological; D045162:Thiazolidinediones / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D000077602:Tolvaptan; D000077288:Troglitazone
chemical_list: D001552:Benzazepines; D002839:Chromans; D045162:Thiazolidinediones; D000077602:Tolvaptan; D000077288:Troglitazone
keywords: Adaptive immune system; Computer modeling; Idiosyncratic DILI; Liver injury; Quantitative systems pharmacology