Data-driven approach for cross-species comparative metabolite exposure assessment: how to establish fundamental...

We previously developed an high-performance LC-MS peak area ratio approach to demonstrate whether an animal species used in a toxicology study has greater exposures to drug metabolites relative to humans, meeting regulatory guidances regarding safety assessment of drug metabolites. Herein we explain the underlying bioanalytical principals, how to establish all fundamental bioanalytical parameters, and how to evaluate data quality in sample analysis, in the absence of authentic standards of analyte(s). A data-driven tiered approach was used in which data from the peak area ratio method can stand based on statistical analysis, as well as assuring that fundamental elements of bioanalytical method and bioanalysis are met. This strategy offers considerable time- and resource-saving advantage while providing high confidence in the safety assessment of human metabolites in drug development.