Pharmacogenetic Analysis of Topiramate Treatment of AUD

托吡酯治疗 AUD 的药物遗传学分析

基本信息

批准号：
9315606
负责人：
HENRY RICHARD KRANZLER
金额：
$ 52.01万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9315606
关键词：
3&apos Untranslated Regions Adverse effects Affect Alcohol dependence Alcoholic beverage heavy drinker Alcohols Alleles American Anticonvulsants Biological Body Weight decreased Clinical DSM-V Data Collection Disease Disulfiram Enrollment Ensure Enzymes Epilepsy Equipment and supply inventories European Evidence based treatment Expectancy FDA approved Formulation Foundations Frequencies Gene Frequency Gene Proteins Genes Genetic Genetic Enhancement Genotype Goals Government Agencies Healthcare Systems Heavy Drinking Homozygote Individual Injectable Kainic Acid Receptors Label Link Measures Meta-Analysis Migraine Minor Monitor Naltrexone National Institute on Alcohol Abuse and Alcoholism Neurotransmitters Ondansetron Oral Outcome Patient Self-Report Patients Pharmaceutical Preparations Pharmacogenetics Pharmacologic Substance Placebos Population Prevalence Process Prospective Studies Public Health Quality of Care Randomized Randomized Clinical Trials Receptor Gene Recommendation Relapse Reporting Single Nucleotide Polymorphism Telephone Testing United States acamprosate adverse outcome alcohol abuse therapy alcohol effect alcohol expectancy alcohol use disorder base clinical application design drinking drinking behavior efficacy study expectation experience improved innovation mu opioid receptors open label personalized care personalized medicine personalized pharmacotherapy placebo controlled study prevent promoter prospective public health relevance responders and non-responders response serotonin transporter success topiramate treatment trial unnecessary treatment

项目摘要

DESCRIPTION (provided by applicant): Alcohol dependence (AD), which is highly prevalent in the United States, is rarely treated with medications approved by the FDA. Concerted efforts to promote the use of the three FDA-approved medications for AD have had limited success, largely because of their modest efficacy. The anticonvulsant topiramate (TOP), though not approved to treat AD, substantially reduced the frequency of heavy drinking (HD) in four placebo-controlled trials and two open-label studies. Based on these findings, TOP is increasingly being prescribed off-label to treat AD (e.g., in the VA Healthcare System). Recently, we found that the ability of TOP to reduce HD was limited to individuals with the CC genotype of rs2832407, a single nucleotide polymorphism (SNP) in GRIK1, the gene encoding the kainate receptor GluK1 subunit. This finding for TOP adds to similar Pharmacogenetics findings for two other medications to treat AD, the beneficial effects of which are substantially enhanced by genetic moderators: naltrexone (which is moderated by a SNP in the mu-opioid receptor gene, OPRM1) and ondansetron (which is moderated by two genotypes in SLC6A4, the serotonin transporter gene). Consistent with the goal of personalized treatment for AD, these findings would allow clinicians to identify, in advance, which patients are likely to respond to each of these medications and which should be spared the unnecessary adverse effects that may accompany treatment in a likely non-responder. Of note, together, these three Pharmacogenetics findings would make it possible to select the best medication to reduce HD in ~75% of European Americans. METHODS: To advance the effort to develop personalized pharmacotherapy for alcohol use disorders (AUDs), we propose to conduct a 12-week, prospective, randomized clinical trial of the moderating effect of rs2832407 on the efficacy of TOP in reducing HD in 200 individuals of European descent with DSM-5 AUD. We will stratify the randomization on genotype and oversample rs2832407*C homozygote's, the most TOP-responsive genotype, to ensure comparable numbers of patients in the four medication x genotype groups. We will use daily data collection to examine changes in relevant process variables (e.g., alcohol expectancies) and their interaction with genotype and medication group as predictors of HD. The proposed study is innovative in that it will be the first prospective tes of a Pharmacogenetics hypothesis involving TOP: it will use daily reports to examine expectancies and how they interact with medication and genotype to predict HD~ and it will enroll DSM-5 AUD patients whose goal is either to reduce or stop drinking, which will increase the study's external validity. PUBLIC HEALTH IMPACT: The capacity to differentiate, in advance, likely responders from non-responders to a medication such as TOP would substantially enhance the efficacy of alcohol treatment, avoid unnecessary adverse effects, and improve the quality of care for AUD. It would also likely increase the use of a highly efficacious medication to treat AUD, which is currently undertreated and for which evidence-based treatment is underutilized.

描述（由申请人提供）：在美国高度普遍的酒精依赖（AD）很少接受FDA批准的药物治疗。一致促进使用三种FDA批准的广告的努力取得了有限的成功，这主要是因为它们的效力适中。抗惊厥药（顶部）虽然未批准治疗AD，但在四项安慰剂对照试验和两项开放标签研究中大大降低了重饮用频率（HD）。基于这些发现，越来越多地在标签外处方以治疗AD（例如，在VA医疗保健系统中）。最近，我们发现TOP降低HD的能力仅限于具有rs2832407的CC基因型，即GRIK1中的单核苷酸多态性（SNP），这是编码Kainate受体GLUK1亚基的基因。对于TOP的这一发现增加了其他两种治疗AD的药物遗传学发现，其有益作用可通过遗传调节剂来增强：Naltrexone：Naltrexone（由SNP调节MU-阿普特受体基因中的SNP，OPRM1）和Ondansetron（由SLCC66A中的两个基因型），SEROTYETER SEROTERSERS，该基因构成。这些发现与AD的个性化治疗的目标一致，这些发现将使临床医生可以提前确定患者可能会做出反应对于这些药物中的每种药物，应保留可能伴随可能无反应者的治疗伴随的不必要的不良影响。值得注意的是，这三种药物遗传学发现将使选择最佳药物以减少约75％的欧洲裔美国人的HD。方法：为了促进开发针对酒精使用障碍的个性化药物治疗（AUDS）的努力，我们建议进行为期12周的，前瞻性，随机的临床试验，以了解RS2832407对TOP在200个使用DSM-5 AUD的200个个体中TOP在200个个体中降低HD效力的调节作用。我们将对基因型上的随机分类，并过度样品RS2832407*C纯合子（最响应性的基因型），以确保四种药物X基因型组中的患者数量可比数量。我们将使用每日数据收集来检查相关过程变量（例如，酒精预期）的变化及其与基因型和药物组的相互作用作为HD的预测因子。拟议的研究具有创新性，因为它将是涉及顶部的药物遗传学假设的第一个前瞻性TE：它将使用每日报告来检查预期以及它们与药物和基因型如何相互作用以预测HD〜，并且它将招募DSM-5 AUD患者，其目标是减少研究或停止饮酒的目标，这将增加研究的外部验证。公共卫生的影响：事先区分从无反应者到TOP等药物的反应者的能力将大大提高酒精治疗的功效，避免不必要的不良反应，并提高AUD的护理质量。这也可能会增加使用高效的使用治疗AUD的药物，目前未治疗的AUD且基于证据的治疗未被充分利用。