Abstracts

Rationale: Retigabine (RTG) is the first AED to act as neuronal KCNQ channel opener to enhance M-current regulation of neuronal excitability. Double-blind, placebo-controlled trials have established 600-1200 mg/day RTG as effective adjunctive therapy in adults with partial-onset seizures. RTG is extensively metabolized by hepatic hydrolysis/acetylation and glucuronidation but does not inhibit or induce Phase 1 or Phase 2 metabolism. Elimination of parent and metabolites is primarily renal. This open-label study assesses the impact of renal impairment on RTG pharmacokinetics. Methods: Study participants are patients with chronic stable renal disease categorized as mild (creatinine clearance, 50-80 mL/min), moderate (30-<50 mL/min), severe (<30 mL/min) or requiring dialysis and healthy volunteers matched for age, gender, and body weight. All subjects received a single 100-mg RTG tablet after overnight fast. Blood and urine concentrations were determined in samples collected before and at multiple times during a 4-day post-dosing interval. Results: Based on data from 26 subjects (mild renal disease, N=5; moderate, N=5; severe, N=4; dialysis, N=6; healthy volunteers, N=6), clearance (CL/F and CLR) decreased with increasing degree of renal impairment. Relative to healthy subjects, CL/F was reduced ~25% in subjects with mild renal impairment and ~50% in patients with moderate or severe renal impairment or in those patients who required dialysis. Similarly, CLR decreased ~25%, 50%, and 70% in subjects with mild, moderate, or severe renal impairment, respectively. These changes resulted in a 30% increase in RTG AUC in subjects with mild renal impairment and ~100% AUC increases in subjects with moderate or severe renal impairment or in those requiring dialysis. Mean T1/2 values increased with increasing severity of renal impairment from 8 hrs in healthy subjects to 23 hrs in subjects requiring dialysis. Conclusions: RTG exposure is increased and plasma and renal clearance are decreased as severity of renal impairment increases. Relative to healthy subjects, RTG exposure is increased ~30% with mild impairment and ~100% with moderate or severe impairment and in individuals requiring dialysis. Funded by Valeant Pharmaceuticals International.