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Evaluation of the Relative Performance of Drug-Induced Skeletal Muscle Injury Biomarkers in Rats.
Toxicol Sci 2016; 150(1):247-56TS

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+Show Affiliations

*Pfizer, Inc. Worldwide Research & Discovery, Groton,Connecticut 06340;Eli Lilly & Co., Indianapolis,Indiana 46225;Critical Path Institute, Predictive Safety Testing Consortium, Tucson, Arizona 85718;Abbvie Inc., Wyandotte, Michigan 48192;*Pfizer, Inc. Worldwide Research & Discovery, Groton,Connecticut 06340;*Pfizer, Inc. Worldwide Research & Discovery, Groton,Connecticut 06340;Eli Lilly & Co., Indianapolis,Indiana 46225;Critical Path Institute, Predictive Safety Testing Consortium, Tucson, Arizona 85718;Merck Research Laboratories, West Point, Pennsylvania 19486;Critical Path Institute, Predictive Safety Testing Consortium, Tucson, Arizona 85718;Merck Research Laboratories, West Point, Pennsylvania 19486;Merck Research Laboratories, West Point, Pennsylvania 19486;Eli Lilly & Co., Indianapolis,Indiana 46225;Merck Research Laboratories, West Point, Pennsylvania 19486;Eli Lilly & Co., Indianapolis,Indiana 46225;Bristol-Myers Squibb, Princeton, New Jersey 08540.Genentech, Inc., South San Francisco, California 94080; and.Merck Research Laboratories, West Point, Pennsylvania 19486; warren_glaab@merck.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26721300

Citation

Burch, Peter M., et al. "Evaluation of the Relative Performance of Drug-Induced Skeletal Muscle Injury Biomarkers in Rats." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 150, no. 1, 2016, pp. 247-56.
Burch PM, Greg Hall D, Walker EG, et al. Evaluation of the Relative Performance of Drug-Induced Skeletal Muscle Injury Biomarkers in Rats. Toxicol Sci. 2016;150(1):247-56.
Burch, P. M., Greg Hall, D., Walker, E. G., Bracken, W., Giovanelli, R., Goldstein, R., ... Glaab, W. E. (2016). Evaluation of the Relative Performance of Drug-Induced Skeletal Muscle Injury Biomarkers in Rats. Toxicological Sciences : an Official Journal of the Society of Toxicology, 150(1), pp. 247-56. doi:10.1093/toxsci/kfv328.
Burch PM, et al. Evaluation of the Relative Performance of Drug-Induced Skeletal Muscle Injury Biomarkers in Rats. Toxicol Sci. 2016;150(1):247-56. PubMed PMID: 26721300.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of the Relative Performance of Drug-Induced Skeletal Muscle Injury Biomarkers in Rats. AU - Burch,Peter M, AU - Greg Hall,David, AU - Walker,Elizabeth G, AU - Bracken,William, AU - Giovanelli,Richard, AU - Goldstein,Richard, AU - Higgs,Richard E, AU - King,Nicholas M P, AU - Lane,Pamela, AU - Sauer,John-Michael, AU - Michna,Laura, AU - Muniappa,Nagaraja, AU - Pritt,Michael L, AU - Vlasakova,Katerina, AU - Watson,David E, AU - Wescott,Debra, AU - Zabka,Tanja S, AU - Glaab,Warren E, Y1 - 2015/12/31/ PY - 2016/1/2/entrez PY - 2016/1/2/pubmed PY - 2016/12/15/medline KW - biomarkers KW - creatine kinase M isoform KW - fatty acid binding protein 3 KW - myosin light chain 3 KW - qualification KW - skeletal muscle KW - skeletal troponin I SP - 247 EP - 56 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol. Sci. VL - 150 IS - 1 N2 - 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. SN - 1096-0929 UR - https://www.unboundmedicine.com/medline/citation/26721300/Evaluation_of_the_Relative_Performance_of_Drug_Induced_Skeletal_Muscle_Injury_Biomarkers_in_Rats_ L2 - https://academic.oup.com/toxsci/article-lookup/doi/10.1093/toxsci/kfv328 DB - PRIME DP - Unbound Medicine ER -