title: The Promise of New Technologies to Reduce, Refine, or Replace Animal Use while Reducing Risks of Drug Induced Liver Injury in Pharmaceutical Development.
abstract: Drug induced liver injury (DILI) has contributed more to marketed pharmaceutical withdrawals and clinical development failures than any other human organ toxicity. DILI seen in animal studies also frequently leads to the discontinuation of promising drug candidates very early in the pipeline. This manuscript reviews and critically assesses the current regulatory expectations; the current drug development approaches, strategies, and gaps; and the numerous exciting opportunities becoming available to address these gaps through technological advances. Emerging integrated pharmaceutical development strategies, while far from uniform, have generally evolved to currently inform early DILI risk potential using supplemental assays for reactive metabolite formation, mitochondrial toxicity, inhibition of bile salt transport, and cellular imaging endpoints including cytotoxicity. Despite these approaches and robust animal testing, significant gaps in addressing human DILI remain. Increasingly sophisticated in vitro humanized test systems, new animal models, emerging computational models, and novel translational biomarkers are being introduced to improve our ability to more accurately predict DILI. Expectations are high for a future state with more predictive tools and problem solving strategies that will improve pharmaceutical discovery and development in relation to understanding human DILI risk potential and make it less dependent on animal studies for successfully developing safer drug candidates.
authors.affiliation: Frank D. Sistare, PhD, is Associate Vice President, Safety Assessment and Laboratory Animal Resources at Merck and Co., Inc. in West Point, PA. William B. Mattes, PhD, DABT, is Director, Division of Systems Biology at the Food and Drug Administration's National Center for Toxicological Research in Jefferson, AR. Edward L. LeCluyse, PhD, is Principal Scientist at LifeNet Health in Research Triangle Park, NC.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Sistare
authors.affiliation: Frank D. Sistare, PhD, is Associate Vice President, Safety Assessment and Laboratory Animal Resources at Merck and Co., Inc. in West Point, PA. William B. Mattes, PhD, DABT, is Director, Division of Systems Biology at the Food and Drug Administration's National Center for Toxicological Research in Jefferson, AR. Edward L. LeCluyse, PhD, is Principal Scientist at LifeNet Health in Research Triangle Park, NC.
authors.forename: William B
authors.initials: WB
authors.lastname: Mattes
authors.affiliation: Frank D. Sistare, PhD, is Associate Vice President, Safety Assessment and Laboratory Animal Resources at Merck and Co., Inc. in West Point, PA. William B. Mattes, PhD, DABT, is Director, Division of Systems Biology at the Food and Drug Administration's National Center for Toxicological Research in Jefferson, AR. Edward L. LeCluyse, PhD, is Principal Scientist at LifeNet Health in Research Triangle Park, NC.
authors.forename: Edward L
authors.initials: EL
authors.lastname: LeCluyse
mesh_terms: D032761:Animal Experimentation; D023401:Animal Use Alternatives; D000818:Animals; D015415:Biomarkers; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans
chemical_list: D015415:Biomarkers
keywords: computational model; drug induced liver injury; hepatocyte; high-content screening; in vitro; liver biomarkers; predictive toxicology