Pharmacogenetic Analysis of Topiramate Treatment of AUD

托吡酯治疗 AUD 的药物遗传学分析

• 批准号: 8748792
• 负责人: HENRY RICHARD KRANZLER
• 金额: $ 53.98万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/8748792
• 关键词: 3' Untranslated Regions; Adverse effects; Affect; Alcohol dependence; Alcoholic beverage heavy drinker; Alcohols; Alleles; American; Anticonvulsants; Biological; Body Weight decreased; Caring; Carrier Proteins; Data Collection; Diagnostic and Statistical Manual of Mental Disorders; Disease; Disulfiram; Drug Formulations; Enrollment; Ensure; Enzymes; Epilepsy; Equipment and supply inventories; European; Evidence based treatment; Expectancy; FDA approved; Foundations; Frequencies; Gene Frequency; Genes; Genetic; Genotype; Goals; Health; 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; Opioid; Oral; Outcome; Patient Self-Report; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacologic Substance; Pharmacotherapy; Placebos; Population; Prevalence; Process; Prospective Studies; 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; expectation; experience; improved; innovation; open label; placebo controlled study; prevent; promoter; prospective; public health relevance; response; serotonin transporter; success; topiramate; treatment trial

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。 共同努力，以促进使用三种FDA批准的药物治疗AD的成功有限，主要是因为它们的疗效有限。 抗惊厥药托吡酯（TOP）虽然没有被批准用于治疗AD，但在四项安慰剂对照试验和两项开放标签研究中大大减少了大量饮酒（HD）的频率。 基于这些发现，TOP越来越多地被用于标签外治疗AD（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rs 2832407 CC基因型的个体，rs 2832407是GRIK 1中的单核苷酸多态性（SNP），GRIK 1是编码红藻氨酸受体GluK 1亚基的基因。 TOP的这一发现增加了其他两种治疗AD的药物的类似药物遗传学发现，其有益效果通过遗传调节剂大大增强：纳洛酮（由μ阿片受体基因OPRM 1中的SNP调节）和昂丹司琼（由SLC 6A 4中的两种基因型调节，血清素转运蛋白基因）。 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有反应 这些药物中的每一种，并且应该避免可能伴随可能无应答者的治疗的不必要的不良反应。 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好的药物来减少约75%的欧洲裔美国人的HD。 方法：为了推进酒精使用障碍（AUDs）的个性化药物治疗，我们建议进行一项为期12周的前瞻性随机临床试验，研究rs 2832407对TOP降低200名欧洲血统DSM-5 AUD患者HD的疗效的调节作用。 我们将根据基因型对随机化进行分层，并对rs 2832407 *C纯合子（最具TOP反应的基因型）进行过采样，以确保4个药物x基因型组中的患者数量相当。 我们将使用日常数据收集来检查相关过程变量的变化（例如，酒精期望）及其与基因型和药物组的相互作用作为HD的预测因子。 这项拟议的研究是创新的，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来预测HD，它将招募DSM-5 AUD患者，他们的目标是减少或停止饮酒，这将增加研究的外部有效性。对公众健康的影响：提前区分药物（如TOP）的可能应答者和无应答者的能力将大大提高酒精治疗的疗效，避免不必要的不良反应，并提高AUD的护理质量。 它也可能增加使用一种高效的 治疗AUD的药物，目前治疗不足，循证治疗利用不足。