Abstracts

Rationale: Retigabine (RTG; ezogabine in North America) is a first-in-class AED that reduces neuronal excitability by enhancing the activity of KCNQ (Kv7) K channels. In preclinical toxicology studies, RTG was shown to inhibit urinary bladder contraction, with these effects considered the result of a direct pharmacological effect at additional KCNQ channels, potentially KCNQ5 or KCNQ3/4, expressed in urinary bladder smooth muscle. These preclinical findings have been extensively evaluated in the clinical program. Here we summarize the safety profile of RTG associated with bladder function from an integrated dataset of Phase 2 and 3 clinical studies (data as of October 2, 2009). Methods: Renal/urinary safety was assessed in RTG-treated patients from 5 completed Phase 2 (Studies 200/201, 202, 205, 209, and 214), 2 completed Phase 3 (RESTORE 1/Study 301 [NCT00232596] and RESTORE 2/Study 302 [NCT00235755]), 4 completed long-term open-label extension (LTOLE; Studies 208, 212, 216, and 8017), and 2 ongoing LTOLE (Studies 303 [NCT00310375] and 304 [NCT00310388]) studies. Safety evaluations of bladder function included adverse events (AEs) related to urinary retention/voiding dysfunction, assessments of American Urological Association Symptom Index (AUA SI) scores and postvoid residual (PVR) volume. Results: A total of 1365 patients were exposed to RTG (most at 900 to <1200 mg/day), with a median total exposure of 261 days. Voiding dysfunction and urinary retention-related AEs were reported by 118 (8.6%) patients, including urinary hesitation (3.1%), urinary retention (1.9%), and residual urine volume (1.2%). Serious AEs of urinary retention were reported by 4 patients and 5 patients required urinary bladder catheterization. Urinary hesitation and retention led to discontinuation in 1 (<0.1%) and 6 (0.4%) patients, respectively. Urinary symptoms generally remitted following discontinuation of RTG, suggesting reversibility consistent with a pharmacological effect. To put these data in context, the incidences of urinary hesitation, urinary retention, and residual urine volume in placebo-treated patients in the Phase 2/3 randomized controlled trials (n=427) were 0.9% (4 patients), 0.5% (2 patients), and 0.2% (1 patient), respectively. AUA SI scores generally remained consistent and low (?7: mild). PVR values of potential clinical concern were reported by 55 of 642 (9%) evaluable patients, 9 for whom PVR values were of concern at baseline. Conclusions: RTG can exert a pharmacological effect on bladder function as evidenced by voiding dysfunction and urinary retention-related AEs and, in those patients evaluated, a slight but reversible increase in PVR volume. Importantly, the majority of these AEs were mild with most patients able to continue treatment without difficulties. However, caution should be taken in patients at risk of urinary retention. While RTG may affect human bladder function leading to urinary retention in a small number of patients, the data do not suggest an irreversible effect of RTG on bladder function. Funded by Valeant Pharmaceuticals International and GlaxoSmithKline.