Neurogenic bladder (NGB) following spinal cord compromise presents a significant clinical challenge. Characterized by disrupted neural control of bladder and sphincter functions, NGB evolves from initial detrusor hyperreflexia and sphincter dyssynergia to chronic atrophy and fibrosis.¹

NGB management is critically predicated on maintaining low bladder-storage pressures to preserve upper urinary tract function and prevent complications such as neurogenic detrusor overactivity, urinary incontinence (UI), urinary tract infections and urosepsis, and renal failure. Comprehensive assessments using urodynamic studies, postvoid residual measurements, and imaging are essential in guiding medical and surgical therapies. Current hallmarks of NGB management include intermittent catheterization and systemic pharmacologic agents, such as anticholinergics and/or β3 adrenergic agonists, which are hampered by inconsistent therapeutic adherence and potentially a partial modulation of underlying targets. Globally, these early management strategies can result in infection, local and upper tract tissue damage, and the exacerbation of neurogenic bowel and cardiovascular symptoms.

Yet, efforts to circumvent these barriers are often more invasive and adverse. For example, intravesical botulinum toxin injections carry a transient therapeutic benefit necessitating recurrent anesthesia exposure in children.² Augmentation cystoplasty is also associated with significant surgical, metabolic, and oncologic risks.³ Therefore, there is a critical need for a minimally invasive, effective, and targeted solution that enhances therapeutic adherence, improves symptom control, localizes treatment to the bladder, and reduces systemic side effects and morbidity. We seek to develop an intravesical long-term drug-delivery platform that addresses these needs.

Trospium chloride (TrCl) is a competitive muscarinic receptor antagonist with minimal central nervous system penetration due to its large molecular size and polarity. Such attributes reduce the risk of cognitive side effects, which are otherwise common with other anticholinergics like oxybutynin. In clinical trials, a 20 mg oral dose of TrCl taken twice daily significantly improved NGB management, increasing bladder capacity, reducing detrusor pressure, and enhancing compliance.⁴

While it has relative benefits compared to other anticholinergics, TrCl still exerts significant systemic side effects. Yet, it also presents a unique pharmacokinetic profile that makes it preferable to other anticholinergics in the context of intravesical administration. For instance, TrCl is known for its poor oral bioavailability, which is less than 10%, and its absorption is further reduced by food intake.⁵ Furthermore, TrCl is predominantly eliminated from the body in its unchanged form through renal excretion. As such, intravesical delivery of TrCl offers the advantage of high local bladder concentrations with minimal systemic absorption.⁶

Studies on single intravesical TrCl instillations in NGB patients indeed demonstrated minimal systemic absorption and substantial local efficacy.⁷ Controlled-release drug delivery systems using TrCl-loaded polymer carriers have demonstrated significant reductions in spontaneous bladder contractions in porcine models.⁸ Perhaps the most convincing evidence regarding long-term intravesical TrCl delivery came from a recent clinical trial in which a novel intravesical silicone device was preloaded with 800 mg of TrCl for managing nonneurogenic overactive bladder.⁹ Congruent with preclinical findings indicating that the device could generate high local TrCl concentrations with minimal systemic absorption, trial results showed that the device produced local urine TrCl levels significantly higher than oral dosing with negligible systemic exposure. Subjects reported a 75% reduction in UI episodes as well as significant improvements in quality of life. While some adverse effects, such as hematuria and bladder discomfort, were noted, the study concluded that continuous exposure to supratherapeutic levels of TrCl for 6 weeks was safe, well-tolerated, and effective in reducing UI episodes and enhancing patient quality of life.

From all of this, we plan to use a rodent spinal cord injury model of NGB and TrCl as a test pharmacologic agent to assess 3 key aspects vital to the creation of any drug-delivery system (timing, dosing, and frequency) and their effects on bladder compliance, neurogenic detrusor overactivity, and UI. Building on prior experience evaluating rodent bladders via cystometry,¹⁰ we hypothesize that (1) early TrCl therapy, (2) supratherapeutic intravesical TrCl dosing, and (3) continuous intravesical TrCl delivery will improve NGB functional outcomes.

The AUA/Urology Care Foundation™ Research Scholars Award affords us the meaningful opportunity to work with motivated colleagues to investigate ways to improve upon the current standards of care. By developing a novel intravesical drug-delivery platform, we hope to enhance therapeutic adherence, improve bladder compliance, and reduce the need for invasive procedures. We also hope to better understand the pathogenesis of NGB and how intravesical treatments can alter the disease course. Most importantly, the successful implementation of this platform in NGB patients could result in significantly improved outcomes, diminished complications, and an enhanced quality of life.