权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Interindividual Variability in Drug Metabolism in Ethnically Diverse Populations

不同种族人群中药物代谢的个体差异

基本信息

批准号：
10439857
负责人：
Klarissa D Jackson
金额：
$ 38.18万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10439857
关键词：
Address Affect Age Award Biological Markers Clinical Cytochrome P450 Data Dose Drug Interactions Drug Kinetics Enzymes Ethnic Origin Ethnic group European Foundations Genes Genetic Genetic Markers Genotype Goals Individual Investigation Investments Laboratories Mentors Patient Rights Patients Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacotherapy Phenotype Population Population Heterogeneity Precision Medicine Initiative Proteomics Research Research Personnel Scientist Testing Time Toxic effect Variant Vision Work base drug disposition drug metabolism drug response prediction epigenetic drug epigenomics ethnic diversity genetic variant implementation barriers improved insight inter-individual variation metabolic abnormality assessment metabolomics multiple omics next generation non-genetic patient population pharmacokinetic model phenotypic biomarker physiologically based pharmacokinetics precision medicine predictive modeling programs response sex side effect

项目摘要

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.

项目总结