title: A modified multiparametric assay using HepaRG cells for predicting the degree of drug-induced liver injury risk.
abstract: The approach for predicting the degree of drug-induced liver injury (DILI) risk was investigated quantitatively in a modified multiparametric assay using HepaRG cells. Thirty-eight drugs were classified by DILI risk into five categories based on drug labels approved by the Food and Drug Administration (FDA) as follows: withdrawn (WDN), boxed warning (BW), warnings and precautions (WP), adverse reactions (AR), and no match (NM). Also, WP was classified into two categories: high and low concern. Differentiated HepaRG cells were treated with drugs for 24 h. The maximum concentration was set at 100-fold the therapeutic maximum plasma concentration (Cmax). After treatment with drugs, the cell viability, glutathione content, caspase 3/7 activity, lactate dehydrogenase leakage and albumin secretion were measured. As modified cut-off values of each parameter, the TC50(toxic concentration that decreased the response by 50%) and EC200(effective concentration giving a response equal to 200% of controls) were calculated. In addition, the toxicity score (total sum score of the cytotoxic level of each parameter) was calculated. This modified multiparametric assay showed an 87% sensitivity and 87% specificity for predicting the DILI risk. The toxicity score showed a good predictive performance for WDN, BW and WP (high concern) categories [cut-off: score ≥ 1; area under a receiver operating characteristic curve (ROC-AUC): 0.88], and for WDN and BW categories (cut-off: score ≥ 3; ROC-AUC: 0.88). This study newly indicated that the degree of DILI risk might be predictable quantitatively by assessing the toxicity score in the modified multiparametric assay using HepaRG cells. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Pharmacokinetics and Safety Department, Drug Research Center, Kyoto Research Center, Kaken Pharmaceutical Co., Ltd, Kyoto, Japan.
authors.forename: Takafumi
authors.identifier: 0000-0002-6100-7789
authors.initials: T
authors.lastname: Tomida
authors.affiliation: Pharmacokinetics and Safety Department, Drug Research Center, Kyoto Research Center, Kaken Pharmaceutical Co., Ltd, Kyoto, Japan.
authors.forename: Hayao
authors.initials: H
authors.lastname: Okamura
authors.affiliation: Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
authors.affiliation: Pharmacokinetics and Safety Department, Drug Research Center, Shizuoka Research Center, Shizuoka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Konno
mesh_terms: D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000145:classification; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012680:Sensitivity and Specificity
chemical_list: D004364:Pharmaceutical Preparations
keywords: HepaRG cells; drug-induced liver injury; hepatotoxicity; multiparametric assay; toxicity score