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.
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.