Interindividual Variability in Drug Metabolism in Ethnically Diverse Populations

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PROJECT SUMMARY Differences in drug metabolism between patients can significantly affect drug concentrations in the body and overall drug response (efficacy and toxicity). Advances in pharmacogenomics have improved our understanding of how variations in genes that encode drug metabolizing enzymes (e.g., cytochrome P450 enzymes) affect drug response, primarily in European ancestry populations. However, far less is known about the mechanisms and clinical consequences of genetic and non-genetic factors (sex, age, ethnicity, epigenetics, drug interactions, etc.) that affect drug disposition in patients from understudied ethnic backgrounds. Inadequate representation of diverse ancestral populations in both basic and translational pharmacogenomics and multi-omics studies is a key barrier to the implementation of precision medicine for all patients. Recent findings from my laboratory support the contention that genetic and phenotypic markers are needed to accurately assess individual drug metabolism capacity. The overall vision of my research program is to understand the underlying mechanisms of interindividual variability in drug metabolism and drug response to advance precision medicine in ethnically diverse patient populations. Through this Maximizing Investigators’ Research Award (MIRA R35) for Early Stage Investigators, my research program will address key questions and important challenges in the field through the following distinct and complementary projects. Project 1 will test the hypothesis that the inclusion of diverse genetic ancestry populations in pharmacogenetics studies will provide greater insight into the underlying mechanisms of interindividual variability in drug metabolism and response. Project 2 will test the hypothesis that the application of an integrated pharmaco-omics approach will greatly enhance the ability to precisely quantify drug metabolism capacity in individuals from diverse ethnic backgrounds. Project 3 will test the hypothesis that the incorporation of data from mechanistic drug metabolism studies from understudied ethnic populations will improve the prediction of pharmacokinetic variability using data-informed physiologically based pharmacokinetic models compared to model predictions using European-based “reference” populations. Significance: This research promises to shift the current “one-size-fits-all” drug dosing paradigm by utilizing and integrating population-specific genetic variants and phenotypic biomarkers to accurately quantify individual drug metabolism capacity, a major predictor of drug response, in understudied ethnic populations. My research program will increase the return on investment for precision medicine initiatives by overcoming the barriers that have limited the applicability of European-based genotype-guided dosing. This work will lay the foundation needed to implement the right drug at the right dose for the right patient at the right time. This research represents the first comprehensive pharmaco-omics investigation in understudied ethnic populations to utilize germline genetic markers as well as dynamic epigenomic, proteomic, and metabolomic biomarkers to capture drug metabolism phenotype. I am dedicated to mentoring the next generation of drug metabolism scientists.