Drug Metabolism Genotypes in Clinical Practice

临床实践中的药物代谢基因型

• 批准号: 8621350
• 负责人: Charles M. Stein
• 金额: $ 28.17万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8621350
• 关键词: Adverse drug effect; Affect; Alleles; Analgesics; Basic Science; Bioinformatics; CYP2C9 gene; CYP2D6 gene; Caucasians; Caucasoid Race; Clinical; Clinical Trials; Codeine; Computerized Medical Record; DNA; DNA Library; Disease; Dose; Drug Kinetics; Drug Targeting; Drug toxicity; Environment; Enzymes; Epidemiology; Failure; Future; Genes; Genetic; Genetic Variation; Genotype; Goals; Health; Hemorrhage; Hypoglycemia; Individual; International Normalized Ratio; Life; Link; Measures; Methods; Mission; Morbidity - disease rate; Morphine; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pain; Patient Care; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacotherapy; Phase; Phenotype; Population; Prodrugs; Public Health; Randomized Clinical Trials; Randomized Controlled Trials; Research; Risk; Sampling; Sulfonylurea Compounds; Testing; Therapeutic; Thinking; Thrombosis; Titrations; Toxic effect; Translating; Translational Research; Translations; United States; Variant; Warfarin; Work; base; biobank; clinical care; clinical practice; clinically significant; cost effective; drug efficacy; drug metabolism; enzyme activity; genetic variant; improved; injured; innovation; interest; mortality; novel; novel strategies; public health relevance; response

ABSTRACT There is marked variability in drug response among individuals. This variability poses a major clinical problem by causing decreased drug efficacy or unexpected toxicity. The ability to incorporate predictors of drug efficacy or toxicity into clinical practice would be a major advance. Well-defined genetic variations in drug metabolizing enzymes or drug targets contribute to variability in drug concentration and therefore response. These pharmacogenetic findings define a predictable component of variability in drug response among individuals. However, despite intensive research and robust findings, there has been almost no translation of pharmacogenetic findings into clinical practice. A critical barrier is that the importance of pharmacogenetics has not been demonstrated for important patient outcomes in clinical practice. It is not feasible perform a randomized clinical trial to test the clinical importance of every pharmacogenetic question. We propose a novel approach: to use an electronic medical record (EMR) with de-identified information linked to a DNA biobank to test the clinical importance of pharmacogenetic findings for important outcomes of drug therapy in clinical practice. We will implement this novel approach, demonstrating proof-of-principle for three distinct pharmacogenetic findings. These have been chosen for study because there is already overwhelming evidence of an effect on drug metabolism, and consequently pharmacokinetic or pharmacodynamic measures, but genotyping is not yet routine in clinical care. We will test the hypotheses that: 1) CYP2C9 and VKORC1 variants associated with reduced warfarin dose-requirements are associated with greater fluctuation in INR after the warfarin dose-titration phase; 2) CYP2C9 variants with reduced function are associated with more frequent hypoglycemia with sulfonylureas; 3) CYP2D6 poor- and intermediate-metabolizer patients have reduced analgesic effects after receiving codeine for pain. Our approach is to define clinically important pharmacogenetic questions and to test their clinical importance using a combination of bioinformatic, epidemiologic and genetic expertise in a large EMR of more than 1.5 million patients linked to a DNA bank of >157,719 DNA samples. These studies will have high public health impact, not only in translating pharmacogenetic findings to improved patient care for the drugs studied, but also in developing new approaches to testing the importance of future pharmacogenetic observations in clinical practice.

摘要 不同个体之间的药物反应有明显的差异。这种变异性造成了一个重大的临床问题。 通过导致药物疗效降低或意外毒性。纳入药物疗效预测因子的能力 或者进入临床实践的毒性将是一个重大进步。药物代谢中明确的遗传变异 酶或药物靶标会导致药物浓度的变化，从而导致反应。这些 药物遗传学的发现定义了个体间药物反应可变性的可预测成分。 然而，尽管进行了密集的研究和强有力的发现，但几乎没有翻译成 临床实践中的药物遗传学发现。一个关键的障碍是药物遗传学的重要性 没有在临床实践中证明对重要的患者结果是正确的。执行以下操作不可行 随机临床试验，以检验每个药物遗传学问题的临床重要性。我们提议写一部小说 方法：使用带有与DNA生物库链接的未识别信息的电子病历(EMR)来 检验药物遗传学发现对临床重要药物治疗结果的临床重要性 练习一下。我们将实施这一新方法，为三个不同的 药物遗传学的发现。之所以选择这些作为研究对象，是因为已经有了压倒性的 对药物新陈代谢产生影响的证据，以及相应的药代动力学或药效学措施； 但基因分型在临床护理中还不是常规做法。我们将检验以下假设：1)CYP2C9和VKORC1 与华法林剂量需求减少相关的变异与INR的更大波动相关 华法林剂量滴定阶段后；2)功能降低的CYP2C9变异与更多的 伴有磺脲类药物的频繁低血糖；3)CYP2D6中低代谢物患者有 在接受可待因止痛后，止痛效果降低。我们的方法是定义临床上重要的 药物遗传学问题，并使用生物信息学、 流行病学和遗传学专业知识在150多万名患者的大型EMR中与 &gt；157719个DNA样本。这些研究将对公共卫生产生重大影响，不仅是在翻译方面 药物遗传学的发现改善了患者对所研究药物的护理，同时也在开发新的药物方面 在临床实践中检验未来药物遗传学观察的重要性的方法。