Key Challenges and Opportunities Associated with the Use of In Vitro Models to Detect Human DILI: Integrated Risk Assessment and Mitigation Plans.
Drug-induced liver injury (DILI) is a major cause of late-stage clinical drug attrition, market withdrawal, black-box warnings, and acute liver failure. Consequently, it has been an area of focus for toxicologists and clinicians for several decades. In spite of considerable efforts, limited improvements in DILI prediction have been made and efforts to improve existing preclinical models or develop new test systems remain a high priority. While prediction of intrinsic DILI has improved, identifying compounds with a risk for idiosyncratic DILI (iDILI) remains extremely challenging because of the lack of a clear mechanistic understanding and the multifactorial pathogenesis of idiosyncratic drug reactions. Well-defined clinical diagnostic criteria and risk factors are also missing. This paper summarizes key data interpretation challenges, practical considerations, model limitations, and the need for an integrated risk assessment. As demonstrated through selected initiatives to address other types of toxicities, opportunities exist however for improvement, especially through better concerted efforts at harmonization of current, emerging and novel in vitro systems or through the establishment of strategies for implementation of preclinical DILI models across the pharmaceutical industry. Perspectives on the incorporation of newer technologies and the value of precompetitive consortia to identify useful practices are also discussed.
UCB BioPharma SPRL, Chemin du Foriest, R9 Building, 1420 Braine-l'Alleud, Belgium.
Franck A
0000-0003-3436-3830
FA
Atienzar
AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Eric A
EA
Blomme
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration (FDA), Jefferson, AR 72079, USA.
Minjun
0000-0002-6453-2351
M
Chen
Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
Philip
P
Hewitt
Drug Safety Consultant, Macclesfield, Cheshire SK11, UK.
J Gerry
JG
Kenna
Sanofi, Bâtiment C. Bernard, 13 Quai Jules Guesdes, Zone B, BP14, 94403 Vitry-sur-Seine Cedex, France.
Gilles
G
Labbe
U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD 20993, USA.
Frederic
F
Moulin
Novartis Pharma AG, Klybeckstrasse 141, 4057 Basel, Switzerland.
Francois
F
Pognan
Hoffmann La-Roche Inc., 4000 Basel, Switzerland.
Adrian B
AB
Roth
School of Life Sciences, University of Applied Sciences Northwestern Switzerland, Gründenstrasse 40, 4132 Muttenz, Switzerland.
Laura
L
Suter-Dick
Ipsen Biosciences Inc., 650 E Kendall Street, Cambridge, MA 02142, USA.
Okechukwu
O
Ukairo
Institut de Recherches Internationales Servier (IRIS), 50 rue Carnot, 92284 Suresnes Cedex, France.
Richard J
RJ
Weaver
Pfizer R&D, Drug Safety Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Yvonne
Y
Will
Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Donna M
DM
Dambach
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