Merging artificial intelligence (AI) and pharmacometrics to elucidate gene-drug interactions linked to clopidogrel responsiveness in Caribbean Hispanic patients

融合人工智能 (AI) 和药理学，阐明与加勒比西班牙裔患者氯吡格雷反应相关的基因药物相互作用

• 批准号: 10626448
• 负责人: Jorge Duconge
• 金额: $ 14.9万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626448
• 关键词: Address; Adenosine Diphosphate; Adverse Drug Experience Report; Adverse drug event; Adverse effects; Affect; Age; Area; Artificial Intelligence; Biochemical; Biological Availability; Blood Platelets; Body mass index; CYP2C19 gene; CYP3A5 gene; Cardiometabolic Disease; Cardiovascular system; Caribbean Hispanic; Characteristics; Cilostazol; Clinical; Clinical Research; Collagen; Coronary Arteriosclerosis; Coronary Artery Bypass; Costs and Benefits; Data; Demographic Factors; Development; Diabetes Mellitus; Disparity; Dose; Drug Combinations; Drug Exposure; Drug Interactions; Drug Kinetics; Effectiveness; Elderly; Environment; Environmental Risk Factor; Ethnic Population; European ancestry; Exclusion; Exposure to; Family history of; Food; Gender; Genes; Genetic; Genetic Load; Genetic Polymorphism; Genetic Risk; Genome; Genotype; Guidelines; Guns; Healthcare; Hematocrit procedure; Heritability; Heterogeneity; High Prevalence; Hispanic Populations; Individual; Inflammation; International; Kidney Failure; Knowledge; Left Ventricular Ejection Fraction; Length; Lesion; Link; Machine Learning; Measurement; Measures; Medical; Medical center; Metabolic; Minority Groups; Modeling; Multivariate Analysis; Myocardial Infarction; Obesity; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacogenomics; Pharmacotherapy; Phenotype; Play; Population; Precision Medicine Initiative; Procedures; Publishing; Purinoceptor; Recommendation; Regimen; Research; Severities; Smoking; Solid; Stents; System; Techniques; Testing; Time; Translating; Underrepresented Populations; United States National Institutes of Health; Up-Regulation; Variant; absorption; acute coronary syndrome; clinical practice; clinically actionable; clinically relevant; clinically significant; clopidogrel; drug response prediction; expectation; falls; frontier; genetic variant; genome wide association study; health care service; health inequalities; high body mass index; hypercholesterolemia; individualized medicine; inhibitor; insight; inter-individual variation; knowledgebase; machine learning method; medically underserved population; metabolic phenotype; non-genetic; novel; percutaneous coronary intervention; pharmacodynamic model; pharmacokinetics and pharmacodynamics; pharmacometrics; population based; precision medicine; predictive modeling; predictive tools; response; risk variant; sound; success; systematic review; treatment response

PROJECT SUMMARY Gene-drug-drug interactions (GDDIs) are becoming a new frontier in Precision Medicine (PM). Pharmacogenomics can certainly be a good predictive tool to guide drug therapies but is far from being a deterministic measure of phenotypes. A current limitation in most of existing guidelines is their lack of provisions to address the effect of drug combinations, co-medications and, therefore, the risk for GDDIs. Although the high inter-individual variability in the response to clopidogrel has primarily been associated with genetic polymorphisms, multivariate analyses suggest that additional factors (e.g., GDDIs) may contribute to the overall between-subject variability in treatment response. However, the extent to which each of these additional factors contributes to the overall variability, and how they are interrelated, is currently unclear. To this purpose, we propose to derive, for the first time ever, a weighted genetic risk score system based on a genome-wide association study in Caribbean Hispanic patients and machine learning methods. We also plan on developing a novel semi-mechanistic population-based pharmacokinetic/pharmacodynamics (PK-PD) modeling of clopidogrel in individuals with GDDIs with cilostazol in order to identify the clinically relevant factors affecting drug exposure and response, which may ultimately serve as a solid basis for dosing optimization and tailoring therapies. Based on strong preliminary data, we hypothesize that: “The enhancing effect of cilostazol over the clopidogrel-induced anti-platelet activity in Caribbean Hispanic patients exposed to these interacting co-medications is exclusive of those who also are CYP2C19 PMs and CYP3A5 non-expressers” This study is expected to provide important new information on the proportions of individuals from the Caribbean Hispanic population who are likely to have combinations of pharmacogenomics variants and exposure to interacting co-medications that may eventually affect their health care. Hispanics have been largely excluded from PM initiatives, which increase dramatically the disparities in translating benefits from new findings in pharmacogenomics to this medically underserved population, exacerbating the existing inequity in healthcare services. Accordingly, the proposed research will expand our current understanding of the PK-PD interactions between clopidogrel and cilostazol from a pharmacogenetics perspective. Advancing knowledge in the under- investigated area of pharmacogenetics in minority populations will generate results that apply to personalize antiplatelet therapy in the wider population as it moves, inevitably, toward increasing heterogeneity through admixed genomes.

项目摘要 基因-药物-药物相互作用（GDDI）正在成为精准医学（PM）的新前沿。 药物基因组学当然可以成为指导药物治疗的良好预测工具，但还远远不能成为一个 表型的确定性测量。大多数现有准则目前的一个局限是缺乏规定 以解决药物组合、合并用药的影响，从而解决GDDI的风险。尽管高 对氯吡格雷反应的个体间变异性主要与遗传相关， 多态性，多变量分析表明另外的因素（例如，GDDI）可能有助于整体 治疗反应的受试者间变异性。然而，这些额外因素中的每一个在多大程度上 目前尚不清楚这两个因素对总体可变性的影响，以及它们之间如何相互关联。为此，我们 我建议推导出，有史以来第一次，加权遗传风险评分系统的基础上，全基因组 加勒比海西班牙裔患者和机器学习方法的关联研究。我们还计划开发一个 氯吡格雷的新型半机制人群药代动力学/药效学（PK-PD）模型 在患有GDDI的患者中使用西洛他唑，以确定影响药物暴露的临床相关因素 和反应，这可能最终作为剂量优化和定制治疗的坚实基础。基于 根据强有力的初步数据，我们假设： “西洛他唑对氯吡格雷诱导的抗血小板活性的增强作用 暴露于这些相互作用的联合用药的患者不包括同时也是CYP 2C 19 PM的患者， CYP 3A 5非表达者” 预计这项研究将提供关于来自加勒比的个人所占比例的重要新资料 可能合并药物基因组学变异和暴露于 相互作用的联合用药，最终可能会影响他们的健康护理。西班牙裔人在很大程度上被排除在外 从PM倡议，这大大增加了差异转化的好处，从新的发现， 药物基因组学对这一医疗服务不足的人群，加剧了现有的医疗保健不公平 服务因此，拟议的研究将扩大我们目前对PK-PD相互作用的理解 氯吡格雷和西洛他唑之间的差异。在知识的推动下， 在少数群体中研究药物遗传学领域将产生适用于个性化的结果， 抗血小板治疗在更广泛的人群中，因为它不可避免地朝着增加异质性的方向发展， 混合基因组