Pharmacodynamics, Pharmacogenetics, Clinical Efficacy and Safety of Tradipitant for Functional Dyspepsia

Tradpitant 治疗功能性消化不良的药效学、药物遗传学、临床疗效和安全性

• 批准号: 10409418
• 负责人: Xiao Jing Wang
• 金额: $ 31.55万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-20 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10409418
• 关键词: Abdomen; Abdominal Pain; Acids; Address; Affect; American; Amitriptyline; Anti-Anxiety Agents; Anti-Cholinergics; Antibiotics; Antidepressive Agents; Antral; Automobile Driving; Complex; Consult; Development; Diagnostic; Discipline of Nuclear Medicine; Disease; Distress; Dyspepsia; Eating; Economics; Epigastric; Escitalopram; FDA approved; Fasting; Functional disorder; Future; G-Protein-Coupled Receptors; Gastric Emptying; Gastrointestinal tract structure; Gastroparesis; General Population; Generations; Genes; Genetic Polymorphism; Health; Helicobacter pylori; Hypersensitivity; Institution; Literature; Measurement; Measures; Medical; Meta-Analysis; Morbidity - disease rate; Nausea; Nausea and Vomiting; Neuraxis; Neuromodulator; Pain; Participant; Patient Outcomes Assessments; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacology; Physicians; Physiological; Placebos; Population; Prevalence; Productivity; Proton Pump Inhibitors; Receptor Activation; Receptor Gene; Reporting; Safety; Satiation; Scanning; Solid; Stomach; Substance P; Substance P Receptor; Symptoms; Syndrome; TAC1 gene; Tachykinin; Techniques; Therapeutic; Variant; Visceral; Workplace; antagonist; aprepitant; base; care seeking; chemotherapy; clinical effect; clinical efficacy; comorbidity; cost; early satiety; economic impact; effective therapy; functional improvement; gastrointestinal function; gastrointestinal symptom; gastrointestinal system; genetic variant; health care service utilization; imaging modality; improved; indexing; non-invasive imaging; novel; patient tolerability; receptor; reduce symptoms; risk benefit ratio; side effect; symptomatic improvement; systematic review; volunteer

ABSTRACT 30 lines (currently 30) Upper gastrointestinal symptoms may result from gastric dysfunction including reduced gastric accommodation and gastric hypersensitivity, and may cause functional dyspepsia (FD), a very common cause of substantial morbidity estimated to affect 10% of the population. FD manifests as abdominal pain/discomfort for at least three days per week which may be associated with eating. An estimated 40% of patients with this symptom complex consult their physicians, negatively influencing their workplace attendance and productivity with overall economic impact of more than $18 billion in 2009. Development of effective treatments of these disorders is desirable, given significant unmet medical need. Systematic reviews and meta-analyses of the literature have shown low levels of efficacy with current treatments which include proton pump inhibitors, H pylori eradication, prokinetics, and central neuromodulators. There is currently no approved treatment for functional dyspepsia. We have developed a noninvasive imaging method to simultaneously measure gastric accommodation and gastric emptying, one or both of which are reported to be altered in up to 75% of patients with functional dyspepsia. The approved NK 1 receptor (NK1R) antagonist aprepitant has been shown to increase fasting gastric volume and postprandial accommodation in healthy participants without deleteriously affecting gastric emptying. The novel NK1R antagonist, tradipitant, was previously shown to reduce symptoms in patients with gastroparesis although the precise mechanism, overall effects, and benefit-risk ratio of this medication unclear. Our general hypothesis is that tradipitant relieves symptoms in patients with functional dyspepsia as well as enhances postprandial gastric accommodation without deleterious effects on gastric emptying. Our aims are: 1. To compare the pharmacodynamics and clinical effects of tradipitant vs. placebo on satiation, fasting and fed gastric volume, gastric accommodation, gastric emptying, and symptoms in patients with functional dyspepsia (and non-delayed gastric emptying at baseline) based on Leuven Dyspepsia scale and Nepean Dyspepsia Index 2. To assess prevalence of NKR-SNP rs881 genetic variant and the pharmacogenetics effects of this variant in NK1 gene on the pharmacodynamics of tradipitant compared to placebo on fasting and accommodation gastric volumes, gastric emptying and satiation. In an exploratory analysis, we shall assess the correlation between gastric accommodation and emptying in functional dyspepsia and to compare the relationship with those previously reported in health volunteers. Anticipated Results and Significance: We expect these studies will lead to understanding the mechanisms of action of tradipitant in improving gastrointestinal functions and patient reported outcomes, including pain, in patients with functional dyspepsia, addressing unmet needs of millions of American citizens.

抽象的 30行（目前30行） 上消化道症状可能是由胃功能障碍引起的，包括胃调节减少 和胃过敏，并可能导致功能性消化不良（FD），这是严重消化不良的一个非常常见的原因 估计影响10%的人口。 FD 表现为腹痛/不适至少持续 每周三天，可能与饮食有关。估计有 40% 的患者有这种症状 复杂的咨询他们的医生，对他们的工作场所出勤率和生产力产生负面影响 2009 年总体经济影响超过 180 亿美元。开发这些疾病的有效治疗方法 鉴于显着的未满足的医疗需求，疾病是可取的。系统评价和荟萃分析 文献表明，目前的治疗方法（包括质子泵抑制剂、H 幽门螺杆菌根除、促动力和中枢神经调节剂。目前尚无批准的治疗方法 功能性消化不良。我们开发了一种无创成像方法来同时测量胃 据报道，高达 75% 的患者其中一项或两项发生改变 伴有功能性消化不良。经批准的 NK 1 受体 (NK1R) 拮抗剂阿瑞匹坦已被证明可以 增加健康参与者的空腹胃容量和餐后调节，且不会产生有害影响 影响胃排空。新型 NK1R 拮抗剂 Tradpitant 先前已被证明可以减轻症状 胃轻瘫患者的确切机制、总体效果和获益风险比 用药不明。我们的一般假设是传统药物可以缓解功能障碍患者的症状 消化不良并增强餐后胃的调节而不会对胃产生有害影响 排空。我们的目标是： 1. 比较传统药物与安慰剂对饱腹感、禁食和食欲的药效学和临床效果。 功能障碍患者的进食胃容量、胃调节、胃排空和症状 基于鲁汶消化不良量表和 Nepean 的消化不良（以及基线时非延迟胃排空） 消化不良指数 2. 评估 NKR-SNP rs881 遗传变异的流行率以及该变异的药物遗传学效应 NK1基因对tradpitant与安慰剂对空腹和胃调节药效学的影响 容量、胃排空和饱腹感。 在探索性分析中，我们将评估胃适应和排空之间的相关性 功能性消化不良，并与之前在健康志愿者中报告的关系进行比较。 预期结果和意义：我们期望这些研究将有助于理解其机制 Tradpitant 在改善胃肠功能方面的作用以及患者报告的结果（包括疼痛） 功能性消化不良患者，解决数百万美国公民未得到满足的需求。