title: Recommendations to qualify biomarker candidates of drug-induced liver injury.
abstract: Certain compounds that induce liver injury clinically are not readily identified from earlier preclinical studies. Novel biomarkers are being sought to be applied across the pharmaceutical pipeline to fill this knowledge gap and to add increased specificity for detecting drug-induced liver injury in combination with aminotransferases (alanine and aspartate aminotransferase)--the current reference-standard biomarkers used in the clinic. The gaps in the qualification process for novel biomarkers of regulatory decision-making are assessed and compared with aminotransferase activities to guide the determination of safe compound margins for drug delivery to humans where monitoring for potential liver injury is a cause for concern. Histopathologic observations from preclinical studies are considered the principal reference standard to benchmark and assess subtle aminotransferase elevations. This approach correlates quite well for many developmental compounds, yet cases of discordance create dilemmas regarding which standard(s) indicates true injury. Concordance amongst a broader set of biomarker injury signals in a qualification paradigm will increase confidence, leading to accepted and integrated translational biomarker signals during safety assessment processes across the pharmaceutical industry, with academia, in government and in contractor laboratories.
authors.affiliation: Pfizer Global Research & Development, Pharmacokinetics, Dynamics & Metabolism, Andover, MA 01810, USA. josef.ozer@pfizer.com
authors.forename: Josef S
authors.initials: JS
authors.lastname: Ozer
authors.forename: Raj
authors.initials: R
authors.lastname: Chetty
authors.forename: Gerry
authors.initials: G
authors.lastname: Kenna
authors.forename: Nandan
authors.initials: N
authors.lastname: Koppiker
authors.forename: Pandher
authors.initials: P
authors.lastname: Karamjeet
authors.forename: Dingzhou
authors.initials: D
authors.lastname: Li
authors.forename: Joe
authors.initials: J
authors.lastname: Palandra
authors.forename: Anne
authors.initials: A
authors.lastname: Lanevschi
authors.forename: Bernard E
authors.initials: BE
authors.lastname: Souberbielle
authors.forename: Shashi
authors.initials: S
authors.lastname: Ramaiah
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood* / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D042241:Early Diagnosis; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D006801:Humans; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D011237:Predictive Value of Tests
chemical_list: D015415:Biomarkers; D007064:L-Iditol 2-Dehydrogenase; D005969:Glutamate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase