Interindividual Variability in Drug Metabolism in Ethnically Diverse Populations

项目摘要 患者之间药物代谢的差异可显著影响体内药物浓度， 总体药物反应（疗效和毒性）。药物基因组学的进步提高了我们对 编码药物代谢酶的基因的变异（例如，细胞色素P450酶）影响药物 主要是欧洲血统的人群。然而，人们对这些机制知之甚少， 遗传和非遗传因素（性别、年龄、种族、表观遗传学、药物相互作用等）的临床后果 这会影响来自未充分研究的种族背景的患者的药物处置。代表性不足 在基础和翻译药物基因组学和多组学研究中， 为所有患者实施精准医疗的关键障碍。我实验室的最新发现 支持需要遗传和表型标记来准确评估单个药物的论点 代谢能力我的研究计划的总体愿景是了解潜在的机制 药物代谢和药物反应的个体间变异性，以推进种族间的精准医学 不同的患者群体。通过这个最大化研究者研究奖（MIRA R35）的早期阶段 调查人员，我的研究计划将通过解决该领域的关键问题和重要挑战， 不同的和互补的项目。项目1将检验这样一个假设， 药物遗传学研究中的遗传祖先群体将提供更深入的了解， 药物代谢和反应的个体间差异机制。项目2将检验假设 综合药物组学方法的应用将极大地提高精确 量化不同种族背景个体的药物代谢能力。项目3将测试 假设将来自未充分研究的种族的机械药物代谢研究的数据合并， 人群将使用基于生理学的数据信息改善药代动力学变异性的预测 药代动力学模型与使用基于欧洲的“参考”人群的模型预测进行比较。 意义：这项研究有望改变目前的“一刀切”的药物给药模式， 整合群体特异性遗传变异和表型生物标志物，以准确定量个体药物 代谢能力，药物反应的主要预测因子，在研究不足的种族人群。我的研究 该计划将通过克服障碍， 限制了基于欧洲基因型指导剂量的适用性。这项工作将奠定基础 需要在正确的时间为正确的患者提供正确剂量的正确药物。这项研究代表 第一次在未充分研究的种族人群中进行全面的药物组学研究， 遗传标记以及动态表观基因组学、蛋白质组学和代谢组学生物标记来捕获药物 代谢表型我致力于指导下一代药物代谢科学家。

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.