URGE

描述（由申请人提供）：急迫性尿失禁（UUI）的特点是不可预测和令人尴尬的大量尿漏，是老年妇女的主要公共卫生负担，因为它的高患病率、生活质量的损害、相关的护理负担和巨大的经济成本。抗胆碱能药物是急迫性尿失禁最常见的一线治疗方法。虽然抗胆碱能药物是有效的，但它们的有效性受到某些个体不良反应或不良事件（ae）的限制。不幸的是，我们无法预测个体患者对抗胆碱能药物的反应，导致经验性药物治疗。药物遗传学是一种个性化药物治疗的新方法。具体来说，非索特罗定是由一种特性良好的细胞色素P450 （CYP）酶CYP2D6代谢的。CYP2D6基因有几个遗传变异，导致不同的代谢状态。这些CYP2D6基因谱可能具有重要的临床意义，因为快速代谢者由于血浆药物浓度低而更有可能产生低疗效，而缓慢代谢者由于血浆药物浓度高而产生ae的风险更高。使用CYP2D6代谢状态来预测哪些受试者对非索罗定会出现低疗效或出现中度至重度不良事件的能力将挑战现有的治疗方法，并将显著推进临床实践。因此，我们的具体目的是：1)评估老年女性UUI患者在4周的非索特罗定治疗期间CYP2D6代谢状态是否与疗效相关；2)评估4周非索罗定治疗期间CYP2D6代谢状态是否与中度至重度不良事件相关。3)利用从该概念验证性试点研究中收集的初步数据，计划一项大规模试验，以CYP2D6代谢状态预测抗胆碱能治疗的结果。这个创新的提议代表了PI珍妮弗·吴博士在衰老研究方面的一个有意义的转变，并将启动她在衰老科学方面的职业生涯，并将建立一个由泌尿妇科医生、老年病医生、药物遗传学家和统计遗传学家组成的多学科合作团队。此外，这项开创性的药物遗传学研究有可能为未来的长期研究奠定基础，为数百万老年妇女优化和个性化UUI治疗。

DESCRIPTION (provided by applicant): Urge urinary incontinence (UUI), characterized by unpredictable and embarrassing large volume urine leakage, is a major public health burden to elderly women given its high prevalence, impairment of quality of life, associated caregiver burden and substantial economic costs. Anticholinergic medications are the most common first-line therapy for urge incontinence. While anticholinergics are efficacious, their effectiveness is limited by poor response or adverse events (AEs) in certain individuals. Unfortunately, we are unable to predict an individual patient's response to anticholinergics, leading to empiric pharmacotherapy. A novel approach to personalize drug therapy is pharmacogenetics. Specifically, fesoterodine is metabolized by a well characterized cytochrome P450 (CYP) enzyme, CYP2D6. The CYP2D6 gene has several genetic variants, which result in different metabolizer statuses. These CYP2D6 profiles may be clinically important because of the greater likelihood of low efficacy in fast metabolizers due to low plasma drug concentrations, and the higher risk of AEs among slow metabolizers due to high drug concentrations. The ability to use CYP2D6 metabolizer status to predict which subjects will experience low efficacy or develop moderate to severe adverse events to fesoterodine would challenge existing therapeutic approaches and would significantly advance clinical practice. Hence, our specific aims are: 1) To evaluate whether CYP2D6 metabolizer status is correlated with efficacy during 4 weeks of fesoterodine therapy in elderly women with UUI; 2) To assess whether CYP2D6 metabolizer status is correlated with moderate to severe adverse events during 4 weeks of fesoterodine therapy, and 3) To utilize preliminary data collected from this proof-of-concept, pilot study to plan a large-scale trial to predict outcomes of anticholinergic therapy based on CYP2D6 metabolizer status. This innovative proposal represents a meaningful shift into aging research for the PI, Dr. Jennifer Wu, and would launch her career into aging science and would establish this multidisciplinary, collaborative team of urogynecologists, geriatricians, pharmacogeneticists and statistical geneticists. Furthermore, this pioneering pharmacogenetic research has the potential to lay essential groundwork for future long-term research which would optimize and personalize UUI therapy for millions of elderly women.