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：
10655317
负责人：
Klarissa D Jackson
金额：
$ 38.16万
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/10655317
关键词：
Affect Age Award Biological Markers Clinical Cytochrome P450 Data Dedications Dose Drug Interactions Drug Kinetics Enzymes Epigenetic Process Ethnic Origin Ethnic Population European European ancestry Foundations Genes Genetic Genetic Markers Genotype Goals Individual Investigation Investments Laboratories Mentors 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 drug disposition drug metabolism drug response prediction 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.

项目摘要患者药物代谢的差异会显着影响体内药物浓度，并且总体药物反应（功效和毒性）。药物基因组学的进步提高了我们的理解关于编码药物代谢酶（例如细胞色素P450酶）的基因的变化如何影响药物反应主要在欧洲血统人群中。但是，关于机制和遗传和非遗传因素（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族裔背景患者的药物处置。不充分的表示在基础和翻译的药物基因组学和多词学研究中，潜水员的祖先种群是一种为所有患者实施精密医学的关键障碍。我实验室的最新发现支持需要遗传和表型标记以准确评估个体药物的论点代谢能力。我的研究计划的总体愿景是了解基本机制药物代谢中的个体变异性和药物对促进精确药物的反应多样化的患者人群。通过最大化研究人员的研究奖（MIRA R35）早期调查人员，我的研究计划将通过该领域的关键问题和重要挑战遵循独特而完整的项目。项目1将检验以下假设药物遗传学研究中的遗传血统种群将为基础提供更深入的洞察力药物代谢和反应中个体变异性的机制。项目2将检验假设应用综合药物词方法的应用将大大提高精确的能力量化来自潜水员背景的个体的药物代谢能力。项目3将测试假设从理解种族的机械药物代谢研究中纳入数据种群将使用基于数据信息的生理学来改善药代动力学变异性的预测与使用基于欧洲的“参考”人群的模型预测相比，药代动力学模型。意义：这项研究有望通过使用和整合人口特异性的遗传变异和表型生物标志物，以准确量化单个药物代谢能力，是药物反应的主要预测指标，在知识的种族中。我的研究计划将通过克服障碍来增加精确医学计划的投资回报率限制了欧洲基因型引导给药的适用性。这项工作将奠定基础需要在正确的时间以正确的剂量为正确的患者实施正确的药物。这项研究代表对知识的种族种类的首次全面的药学投资，以利用种系遗传标志物以及动态表观基因组，蛋白质组学和代谢组生物标志物可捕获药物代谢表型。我致力于为下一代药物代谢科学家进行心理。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Formation of CYP3A-specific metabolites of ibrutinib in vitro is correlated with hepatic CYP3A activity and 4β-hydroxycholesterol/cholesterol ratio.

DOI：
10.1111/cts.13448
发表时间：
2023-02
期刊：
Clinical and translational science
影响因子：
0
作者：
通讯作者：

Metabolism of the Tyrosine Kinase Inhibitor Masitinib In Vitro.

酪氨酸激酶抑制剂马赛替尼的体外代谢。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Latham,Bethany;Jackson,Klarissa;Vergne,MatthewJ
通讯作者：
Vergne,MatthewJ

Impact of Interindividual Variability in CYP3A Activity on Ibrutinib and Venetoclax Metabolism In Vitro.

CYP3A 活性的个体差异对依鲁替尼和维奈托克体外代谢的影响。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Lee,Jonghwa;Jackson,KlarissaD
通讯作者：
Jackson,KlarissaD

Bioactivation and reactivity research advances - 2021 year in review.

DOI：
10.1080/03602532.2022.2097254
发表时间：
2022-08
期刊：
Drug metabolism reviews
影响因子：
5.9
作者：
通讯作者：

Cytosolic Enzymes Generate Cannabinoid Metabolites 7-Carboxycannabidiol and 11-Nor-9-carboxytetrahydrocannabinol.

DOI：
10.1021/acsmedchemlett.3c00017
发表时间：
2023-05-11
期刊：
ACS MEDICINAL CHEMISTRY LETTERS
影响因子：
4.2
作者：
Beers, Jessica L.;Authement, Aurora K.;Isoherranen, Nina;Jackson, Klarissa D.
通讯作者：
Jackson, Klarissa D.