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）：酒精依赖（AD）在美国非常普遍，很少用 FDA 批准的药物治疗。为促进使用 FDA 批准的三种 AD 药物的共同努力取得了有限的成功，这主要是因为它们的疗效有限。抗惊厥药托吡酯 (TOP) 虽然未被批准用于治疗 AD，但在四项安慰剂对照试验和两项开放标签研究中显着降低了酗酒 (HD) 的频率。基于这些发现，TOP 越来越多地被用于治疗 AD 的标签外处方（例如，在 VA 医疗系统中）。最近，我们发现TOP降低HD的能力仅限于具有rs2832407 CC基因型的个体，rs2832407是GRIK1（编码红藻氨酸受体GluK1亚基的基因）中的单核苷酸多态性（SNP）。 TOP 的这一发现补充了其他两种治疗 AD 药物的类似药物遗传学发现，这两种药物的有益效果通过遗传调节剂显着增强：纳曲酮（由 mu-阿片受体基因 OPRM1 中的 SNP 调节）和昂丹司琼（这是由 SLC6A4（血清素转运蛋白基因）中的两种基因型调节的。与 AD 个性化治疗的目标一致，这些发现将使临床医生能够提前确定哪些患者可能会做出反应这些药物中的每一种都应避免在可能无反应的情况下可能伴随治疗而产生不必要的副作用。值得注意的是，这三项药物遗传学研究结果将使我们有可能选择最佳药物来减少约 75% 的欧洲美国人的 HD 发病率。方法：为了推进开发针对酒精使用障碍 (AUD) 的个性化药物疗法，我们建议开展一项为期 12 周的前瞻性随机临床试验，研究 rs2832407 对 TOP 在 200 名个体中减少 HD 的功效的调节作用。欧洲血统，DSM-5 AUD。我们将对基因型进行随机分层，并对 rs2832407*C 纯合子（最具 TOP 反应性的基因型）进行过采样，以确保四个药物 x 基因型组中的患者数量具有可比性。我们将使用日常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 TOP 的药物遗传学假设的第一个前瞻性测试：它将使用每日报告来检查预期以及它们如何与药物和基因型相互作用以预测 HD~ 并将招募 DSM-5 AUD 患者其目标是减少或停止饮酒，这将提高研究的外部有效性。公众健康影响：提前区分 TOP 等药物的可能反应者和无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。它还可能会增加高效药物的使用治疗 AUD 的药物目前治疗不足，且循证治疗未得到充分利用。