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

摘要 30条线（目前为30条） 上消化道症状可能由胃功能障碍引起，包括胃适应性降低 和胃过敏，并可能导致功能性消化不良（FD），一个非常常见的原因， 估计发病率影响10%的人口。FD表现为腹痛/不适至少 每周三天，可能与饮食有关。估计有40%的患者有这种症状 复杂的人咨询医生，对他们的工作场所出勤率和生产力产生负面影响， 2009年的总体经济影响超过180亿美元。开发有效的治疗方法 考虑到显著未满足的医疗需求，疾病是期望的。系统性综述和荟萃分析 文献显示，目前的治疗方法，包括质子泵抑制剂，H 幽门根除、促动力剂和中枢神经调质。目前还没有批准的治疗方法， 功能性消化不良我们已经开发了一种无创成像方法，同时测量胃 调节和胃排空，据报道，高达75%的患者中，其中一种或两种都发生了改变 功能性消化不良已被批准的NK 1受体（NK 1 R）拮抗剂阿瑞匹坦已被证明 增加健康受试者空腹胃容量和餐后调节， 影响胃排空。新的NK 1 R拮抗剂，tradipitant，以前被证明可以减轻症状 尽管在胃轻瘫患者中， 药物不清楚。我们的一般假设是，tradipitant缓解症状的患者， 消化不良以及增强餐后胃适应性，而对胃 清空我们的目标是： 1.比较曲地匹坦与安慰剂对饱食、空腹和 功能性胃肠炎患者的进食胃容量、胃适应性、胃排空和症状 基于Leuven消化不良量表和Neuraly的消化不良（和基线时胃排空未延迟） 消化不良指数 2.评估NKR-SNP rs 881遗传变异的患病率以及该变异在 NK 1基因对曲地匹坦与安慰剂相比在空腹和胃调节方面的药效学的影响 容量、胃排空和饱足。 在探索性分析中，我们将评估胃调节和排空之间的相关性， 功能性消化不良，并与以前报道的健康志愿者的关系进行比较。 预期的结果和意义：我们希望这些研究将有助于了解机制 传统匹坦在改善胃肠道功能和患者报告的结局（包括疼痛）方面的作用， 功能性消化不良患者，解决数百万美国公民未满足的需求。

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.