title: Evaluation of the Relative Performance of Drug-Induced Skeletal Muscle Injury Biomarkers in Rats.
abstract: Novel skeletal muscle (SKM) injury biomarkers that have recently been identified may outperform or add value to the conventional SKM injury biomarkers aspartate transaminase (AST) and creatine kinase (CK). The relative performance of these novel biomarkers of SKM injury including skeletal troponin I (sTnI), myosin light chain 3 (Myl3), CK M Isoform (Ckm), and fatty acid binding protein 3 (Fabp3) was assessed in 34 rat studies including both SKM toxicants and compounds with toxicities in tissues other than SKM. sTnI, Myl3, Ckm, and Fabp3 all outperformed CK or AST and/or added value for the diagnosis of drug-induced SKM injury (ie, myocyte degeneration/necrosis). In addition, when used in conjunction with CK and AST, sTnI, Myl3, CKm, and Fabp3 individually and collectively improved diagnostic sensitivity and specificity, as well as diagnostic certainty, for SKM injury and responded in a sensitive manner to low levels of SKM degeneration/necrosis in rats. These findings support the proposal that sTnI, Myl3, Ckm, and Fabp3 are suitable for voluntary use, in conjunction with CK and AST, in regulatory safety studies in rats to monitor drug-induced SKM injury and the potential translational use of these exploratory biomarkers in early clinical trials to ensure patient safety.
authors.affiliation: *Pfizer, Inc. Worldwide Research & Discovery, Groton,Connecticut 06340;
authors.forename: Peter M
authors.initials: PM
authors.lastname: Burch
authors.affiliation: Eli Lilly & Co., Indianapolis,Indiana 46225;
authors.forename: David
authors.initials: D
authors.lastname: Greg Hall
authors.affiliation: Critical Path Institute, Predictive Safety Testing Consortium, Tucson, Arizona 85718;
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Walker
authors.affiliation: Abbvie Inc., Wyandotte, Michigan 48192;
authors.forename: William
authors.initials: W
authors.lastname: Bracken
authors.affiliation: *Pfizer, Inc. Worldwide Research & Discovery, Groton,Connecticut 06340;
authors.forename: Richard
authors.initials: R
authors.lastname: Giovanelli
authors.affiliation: *Pfizer, Inc. Worldwide Research & Discovery, Groton,Connecticut 06340;
authors.forename: Richard
authors.initials: R
authors.lastname: Goldstein
authors.affiliation: Eli Lilly & Co., Indianapolis,Indiana 46225;
authors.forename: Richard E
authors.initials: RE
authors.lastname: Higgs
authors.affiliation: Critical Path Institute, Predictive Safety Testing Consortium, Tucson, Arizona 85718;
authors.forename: Nicholas M P
authors.initials: NM
authors.lastname: King
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania 19486;
authors.forename: Pamela
authors.initials: P
authors.lastname: Lane
authors.affiliation: Critical Path Institute, Predictive Safety Testing Consortium, Tucson, Arizona 85718;
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Sauer
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania 19486;
authors.forename: Laura
authors.initials: L
authors.lastname: Michna
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania 19486;
authors.forename: Nagaraja
authors.initials: N
authors.lastname: Muniappa
authors.affiliation: Eli Lilly & Co., Indianapolis,Indiana 46225;
authors.forename: Michael L
authors.initials: ML
authors.lastname: Pritt
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania 19486;
authors.forename: Katerina
authors.initials: K
authors.lastname: Vlasakova
authors.affiliation: Eli Lilly & Co., Indianapolis,Indiana 46225;
authors.forename: David E
authors.initials: DE
authors.lastname: Watson
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey 08540.
authors.forename: Debra
authors.initials: D
authors.lastname: Wescott
authors.affiliation: Genentech, Inc., South San Francisco, California 94080; and.
authors.forename: Tanja S
authors.initials: TS
authors.lastname: Zabka
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania 19486; warren_glaab@merck.com.
authors.forename: Warren E
authors.initials: WE
authors.lastname: Glaab
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D052283:Creatine Kinase, MM Form / Q000097:blood; D004305:Dose-Response Relationship, Drug; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins / Q000097:blood; D005260:Female; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009135:Muscular Diseases / Q000097:blood* / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D018994:Myosin Light Chains / Q000097:blood; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012107:Research Design; D012680:Sensitivity and Specificity; D019210:Troponin I / Q000097:blood
chemical_list: D015415:Biomarkers; C509948:FABP3 protein, rat; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D018994:Myosin Light Chains; D004364:Pharmaceutical Preparations; D019210:Troponin I; D052283:Creatine Kinase, MM Form
keywords: biomarkers; creatine kinase M isoform; fatty acid binding protein 3; myosin light chain 3; qualification; skeletal muscle; skeletal troponin I