The process of normal micturition is dependent on neural integration between the central and peripheral nervous systems. In diseases such as multiple sclerosis (MS), impaired neural integration may lead to neurogenic bladder and lower urinary tract dysfunction. Bladder symptoms and the need for catheterization in some patients increase the risk for urinary retention and urinary tract infection (UTI).
Dalfampridine extended release tablets (dalfampridine-ER), 10 mg twice daily, are approved for the improvement of walking in patients with MS. Dalfampridine-ER showed adverse events in the registration trials that included UTI and were reported consistently more frequently in the active treatment groups relative to placebo.2-4 These reports of UTI were based primarily on lower urinary tract symptoms and few cases in either treatment group were confirmed by urine cultures. There is also no clear mechanism for dalfampridine to increase the risk of UTI, particularly given the lack of imbalance between treatment groups for other forms of infection. Thus, it became pertinent to investigate whether dalfampridine-ER exposure increases the risk of actual infections, or whether drug-enhanced local sensory effects may have produced urinary tract symptoms that led to more frequent reports of UTI.
Evidence from two recent clinical studies5,6 showed that treatment with dalfampridine-ER was not associated with an increased risk of UTI compared with placebo. Kantor and colleagues5 utilized 3 types of clinical assessments to determine whether the reported adverse events of lower UTI symptoms in a dalfampridine post-approval study were associated with incidence of actual infection. Accordingly, the confirmation of UTI entailed 1) urinary symptomatology, 2) microscopic urinalysis (presence of ≥5 leukocytes per high-power field), and 3) urine culture for those with symptoms or who had a positive urinalysis. Although a threshold of ≥105 bacterial colony-forming units (CFUs)/mL from urine cultures is generally used to define bacteriuria, counts ≥104 CFUs/mL were also included as a criterion, as a substantial proportion of patients with UTI are known to have colony counts that are <105 CFUs/mL. Regardless of which CFU threshold was used, the proportions of patients who had confirmed UTIs were similar among the groups (4.2% for placebo and 2.8% for both dalfampridine 5 mg and 10 mg, using the >105CFUs/mL threshold; and 4.2%, 3.5%, and 4.9%, respectively, using the >104 CFUs/mL threshold). These proportions of patients with confirmed UTI were lower than the proportions of patients reporting symptoms as adverse events: 5.6%, 6.3%, and 9.9% for placebo and dalfampridine 5 mg and 10 mg, respectively. However, it is important to note that the study excluded patients with active UTI at screening, suggesting that the patients included in the analysis may not necessarily represent the broader MS population.
Additional data on the relationship between dalfampridine-ER and UTI were presented in the MOBILE study that evaluated the long-term treatment effects of dalfampridine-ER on mobility-related outcomes.6 Although urinary symptoms consistent with UTI were reported as adverse events, use of confirmatory cultures determined that the incidence of UTIs was higher in the placebo group (19%) relative to dalfampridine-ER 10 mg twice-daily group (9%).
Based on the totality of the evidence, dalfampridine-ER does not appear to increase the risk of bacteriuria, but the question arises as to the reason for the higher incidence of urinary symptoms reported as adverse events. Dalfampridine-ER is a voltage-gated K+ channel antagonist known to elicit spontaneous neural activity in a concentration-dependent manner.7 Since the drug is primarily excreted in its active form in the urine, it may be that increased concentrations of dalfampridine in the urinary tract result in local sensory effects through stimulation of afferent nerves. Nevertheless, because of the well-recognized risk of neurogenic bladder and UTI in the MS population, confirmatory urine cultures are recommended for those treated with dalfampridine-ER who experience urinary tract symptoms in clinical practice.
References:
1. Ginsberg D. The epidemiology and pathophysiology of neurogenic bladder. Am J Manag Care. 2013;19(10 suppl):s191-s196.
2. Goodman AD, Brown TR, Cohen JA, et al. Dose comparison trial of sustained-release fampridine in multiple sclerosis. Neurology. 2008;71(15):1134-1141.
3. Goodman AD, Brown TR, Krupp LB, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet. 2009;373(9665):732-738.
4. Goodman AD, Brown TR, Edwards KR, et al. A phase 3 trial of extended release oral dalfampridine in mulitple sclerosis. Ann Neurol. 2010;68(4):494-502.
5. Kantor D, Chancellor MB, Snell CW, Henney HR III, Rabinowicz AL. Assessment of confirmed urinary tract infection in patients treated with dalfampridine for multiple sclerosis. Postgrad Med. 2015;127(2):218-222.
6. Hupperts R, Lycke J, Short C, et al. Prolonged-release fampridine and walking and balance in MS: randomised controlled MOBILE trial [published online April 28, 2015]. Mult Scler. doi:10.1177/1352458515581436.
7. Blight AR, Henney HR III, Cohen R. Development of dalfampridine, a novel pharmacologic approach for treating walking impairment in multiple sclerosis. Annals NY Acad Sci. 2014;1329:33-44.
Authors: Adrian L. Rabinowicz, MD, and Andrew R. Blight, PhD. Acorda Therapeutics, Inc., Ardsley, NY
Disclosure: Authors are employees and stockholders of Acorda Therapeutics, Inc.