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

• 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
• 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

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.

项目概要 患者之间药物代谢的差异可显着影响体内药物浓度 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 编码药物代谢酶（例如细胞色素 P450 酶）的基因变异如何影响药物 反应，主要是在欧洲血统人群中。然而，人们对其机制和了解知之甚少。 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 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 在基础和转化药物基因组学和多组学研究中，不同的祖先群体是一个 为所有患者实施精准医疗的主要障碍。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个体药物的论点 新陈代谢能力。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差异，以推进种族精准医学 不同的患者群体。通过早期阶段最大化研究者研究奖（MIRA R35） 调查人员，我的研究计划将通过以下方式解决该领域的关键问题和重要挑战： 遵循独特且互补的项目。项目 1 将检验以下假设： 药物遗传学研究中的遗传祖先群体将提供对潜在的更深入的了解 药物代谢和反应的个体差异机制。项目2将检验假设 综合药物组学方法的应用将大大增强精确 量化不同种族背景个体的药物代谢能力。项目3将测试 假设合并来自未充分研究的种族的机械药物代谢研究的数据 人群将使用基于数据的生理学数据来改进药代动力学变异性的预测 药代动力学模型与使用欧洲“参考”人群的模型预测进行比较。 意义：这项研究有望通过利用和 整合人群特异性遗传变异和表型生物标志物以准确量化个体药物 在未充分研究的种族人群中，新陈代谢能力是药物反应的主要预测因素。我的研究 该计划将通过克服以下障碍来提高精准医疗计划的投资回报 限制了基于欧洲的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以正确的剂量使用正确的药物。这项研究代表 首次利用种系对未受研究的种族人群进行全面的药物组学研究 遗传标记以及动态表观基因组、蛋白质组和代谢组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。

项目成果

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

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。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 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。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 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

Induction of Cytochrome P450 (CYP) 1A2 and CYP3A Influences Sunitinib Metabolism and Bioactivation in Primary Human Hepatocytes.

细胞色素 P450 (CYP) 1A2 和 CYP3A 的诱导影响原代人肝细胞中舒尼替尼的代谢和生物活化。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Jackson,KlarissaD;Lee,Jonghwa;Beers,JessicaL;Nardone-White,DaseanT
• 通讯作者: Nardone-White,DaseanT