Metabolomics-Derived Biomarkers of Drug-Induced Skeletal Muscle Injury and Urinary Bladder Transitional Cell Carcinoma in Rats

Abstract Two biomarker discovery vignettes of work conducted at the Bristol-Myers Squibb laboratories are reported, both illustrating aspects of biomarker utilization and qualification not clearly covered by the evolving regulatory guidance for submission of new biomarkers. Both biomarkers were discovered (or rediscovered) through metabolomic profiling in the context of good laboratory practice (GLP) and non-GLP toxicity studies. Specifically, the first biomarker has utility likely restricted to rats, where its most important usage is in discovery for ranking compound series with respect to potential myopathic liabilities. The second relates to a highly compound-, and possibly pathophysiologic mechanism-specific biomarker for drug-induced urinary bladder transitional cell carcinoma in rats, and the way this biomarker was used to develop a human risk assessment. As the broad cross-species utility or applicability of these biomarkers is improbable, extensive validation as proposed with evolving biomarker qualification guidelines, is difficult to justify for these two biomarkers. The use, however, of these biomarkers within individual research programs is considered highly impactful.