URGE

描述（由申请人提供）：急迫性尿失禁（UUI）的特征是不可预测和令人尴尬的大量尿液渗漏，由于其高患病率、生活质量受损、相关护理人员负担和巨大的经济成本，是老年妇女的主要公共卫生负担。抗胆碱能药物是急迫性尿失禁最常见的一线治疗。虽然抗胆碱能药物是有效的，但其有效性受到某些个体的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。药物遗传学是个体化药物治疗的一种新方法。具体而言，非索罗定通过一种充分表征的细胞色素P450（CYP）酶CYP 2D 6代谢。CYP 2D 6基因有几种遗传变异，导致不同的代谢状态。这些CYP 2D 6特征可能具有临床重要性，因为在快代谢者中，由于血浆药物浓度较低，疗效较低的可能性较大，而在慢代谢者中，由于药物浓度较高，AE风险较高。使用CYP 2D 6代谢者状态来预测哪些受试者将经历低疗效或发生中度至重度非索罗定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，我们的具体目标是：1）评估CYP 2D 6代谢状态是否与非索罗定治疗老年UUI女性4周期间的疗效相关; 2）评估CYP 2D 6代谢状态是否与4周非索罗定治疗期间的中度至重度不良事件相关，以及3）利用从该概念验证中收集的初步数据，计划进行一项大规模试验的初步研究，以根据CYP 2D 6代谢状态预测抗胆碱能药物治疗的结局。这一创新的提议代表了PI Jennifer Wu博士向衰老研究的有意义的转变，并将她的职业生涯推向衰老科学，并将建立这个由妇科泌尿科医生，老年病学家，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，这将为数百万老年妇女优化和个性化UUI治疗。 公共卫生相关性：急迫性尿失禁，其特征是不可预测和尴尬的大量尿液泄漏，是老年妇女的主要健康问题，因为它非常常见，并严重损害生活质量。虽然抗胆碱能药物是最常见的治疗方法，但我们无法预测个体对特定药物的有效性和副作用。通过基因评估，我们有可能为数百万患有急迫性尿失禁的老年妇女提供个性化和优化的药物治疗。

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. PUBLIC HEALTH RELEVANCE: Urge urinary incontinence, characterized by unpredictable and embarrassing large volume urine leakage, is a major health issue for elderly women, as it is incredibly common and significantly impairs quality of life. Although anticholinergic medications are the most common therapy, we are unable to predict an individual's response to a particular drug in terms of both effectiveness and side effects. Through genetic evaluation, we have the potential to personalize and optimize drug therapy for millions of elderly women suffering from urge incontinence.