URGE

描述(由申请人提供)：急迫性尿失禁(UUI)，以不可预测和令人尴尬的大量尿漏为特征，是老年妇女的主要公共卫生负担，因为其发病率高，生活质量下降，相关的照顾者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。虽然抗胆碱药是有效的，但它们的有效性受到某些人不良反应或不良事件(AEs)的限制。不幸的是，我们无法预测单个患者对抗胆碱药物的反应，从而导致经验性药物治疗。一种个性化药物治疗的新方法是药物遗传学。具体地说，非索特罗定是由一种特性良好的细胞色素P450(CYP)酶--细胞色素P450酶CYP2D6基因有几个遗传变异，从而导致不同的代谢物状态。这些CYP2D6图谱可能在临床上很重要，因为在快速代谢者中，由于血浆药物浓度低而疗效低的可能性更大，而在慢代谢者中，由于药物浓度高而发生AEs的风险更高。使用CYP2D6代谢物状态来预测哪些受试者将对非索特罗定产生低疗效或发生中到重度不良事件的能力将挑战现有的治疗方法，并将极大地推动临床实践。因此，我们的具体目标是：1)评估患有UUI的老年女性在接受Fesoterodine治疗4周期间，CYP2D6代谢物状态是否与疗效相关；2)评估CYP2D6代谢物状态是否与Fesoterodine治疗4周期间的中、重度不良事件相关；3)利用从这项概念验证、先导性研究中收集的初步数据，计划进行一项大规模试验，以基于CYP2D6代谢物状态预测抗胆碱能治疗的结果。这项创新的建议代表了PPI Jennifer Wu博士向老龄化研究的有意义的转变，并将开启她在老龄科学领域的职业生涯，并将建立这个由泌尿外科医生、老年医生、药物遗传学家和统计遗传学家组成的多学科协作团队。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必要的基础，这些研究将优化数百万老年妇女的UUI治疗并使其个性化。

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.