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 assessed the impact of hepatic impairment on RTG pharmacokinetics. Methods: Patients with chronic stable liver disease with mild (Child-Pugh score 5-6), moderate (7-9), or severe (>9) hepatic impairment and healthy volunteers matched for age, gender, and body weight 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 4-day post-dosing interval. Results: Data were obtained from 24 subjects (n=6 per group). Clearance (CL/F and CL_R) and AUC were similar in healthy individuals and those with mild hepatic impairment. CL/F was approximately 30% and 50% lower and RTG exposure was approximately 50% and 100% higher in subjects with moderate and severe hepatic impairment, respectively. Approximately 15% of dose was excreted unchanged in urine in all groups; however, between-group CL_R differences mirrored plasma clearance (CL/F) differences. Mean T_1/2 values were similar in all groups and ranged from 6.5 to 8.2 hours. Conclusions: RTG exposure increases and plasma clearance decreases with increasing severity of hepatic impairment. Mild hepatic impairment does not alter RTG pharmacokinetics; moderate and severe hepatic impairment reduce RTG clearance leading to increases in RTG exposure of 50% and 100%, respectively. Funded by Valeant Pharmaceuticals International.