Understanding the Response to Fesoterodine Through Genetic Evaluation in the Elderly

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. UUI is significantly more prevalent in older adults and disproportionately affects women, with a prevalence of 19% in community-dwelling women over 65 and 60-78% in long-term care female residents.

Anticholinergic medications are the most common first-line therapy for UUI. Although numerous trials have demonstrated that anticholinergics are efficacious for UUI, the response to these medications is variable, as their effectiveness is often limited by poor response or adverse events (AEs), such as cognitive impairment or constipation, which are particularly problematic in older adults. Furthermore, a comprehensive systematic review concluded that no one drug is definitively superior, leaving clinicians without any evidence to guide decision-making regarding drug choice. As a result, UUI pharmacotherapy is empiric and not personalized, even though it is clear that individual variations exist in both response and toxicity. The treatment of UUI is especially challenging in the geriatric population, given their higher risk for AEs, polypharmacy, and pharmacokinetic changes that occur with age. The ability to predict which elderly women with UUI will experience low efficacy or develop significant adverse events from anticholinergic medications would be a paradigm shift in the therapeutic practice to this highly prevalent and bothersome condition.

Pharmacogenetics may provide insight into how to predict response to anticholinergic UUI therapy. Research has already shown that genetic differences in drug metabolism impact a patient's drug response. For example, "fast metabolizers" may metabolize the drug so rapidly that therapeutic levels are never reached, limiting effectiveness. In contrast, "slow metabolizers" may develop high drug concentrations, resulting in significantly more AEs. While pharmacogenetic research exists for numerous classes of drugs, including anticoagulants, selective serotonin-reuptake inhibitors,14 beta-blockers, immunosuppressants and opioids, this type of translational research does not exist for anticholinergics for UUI. Thus, this proposed project represents a novel concept and unique opportunity to dramatically change UUI pharmacotherapy.

Fesoterodine is an ideal anticholinergic medication to launch a pharmacogenetic study in this field. Fesoterodine's active metabolite, 5-hydroxymethyl tolterodine (5-HMT), is metabolized by a well-characterized cytochrome P450 (CYP) enzyme, CYP2D6. The CYP2D6 gene has several genetic variants, which result in different metabolizer statuses ranging from poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM), to ultrarapid metabolizers (UM). These different CYP2D6 profiles may be clinically important, as they may contribute to the variability in efficacy and AEs. In fact, pharmaceutical company data for fesoterodine demonstrated that PMs have a two-fold higher plasma concentration than EMs; however, no published data exist on how CYP2D6 metabolizer status correlates with clinical outcomes such as efficacy or AEs. The ability to use CYP2D6 metabolizer status to predict which individuals will experience low efficacy or develop AEs to fesoterodine, and to utilize alternative therapies in these women, would challenge existing therapeutic paradigms and would significantly advance clinical practice via a pharmacogenetic approach.

Specific Aim 1: To explore whether CYP2D6 metabolizer status can predict efficacy during 4 weeks of fesoterodine fumarate therapy in elderly women with UUI. All subjects will be started on fesoterodine 4mg for 2 weeks followed by 8mg for 2 weeks. The primary outcome will be patient-reported treatment response based on a 4-point scale utilized in phase III clinical trials.8,9 We hypothesize that women who rapidly metabolize fesoterodine based on CYP2D6 metabolizer status are more likely to have low efficacy.