Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics and Safety of Carisbamate

This open-label, parallel-group study was designed to characterize the pharmacokinetics (PK) of carisbamate in participants with mild or moderate hepatic impairment versus those with normal hepatic function. Healthy (n = 10) and hepatic-impaired (n = 20) participants received a single 200-mg oral dose of carisbamate. Serial PK blood samples were collected up to 120 hours postdose. A modest increase in mean area under the plasma concentration-time curve from 0 to infinity (AUG(infinity)) was observed for the mild impairment group compared with the normal group (ratio of geometric means similar to 116%), while mean maximum plasma concentration (C-max) values were similar (ratio of geometric means similar to 94%). The AUC(infinity) value for the moderate hepatic-impaired group was approximately 207% that of the normal group, while there was a smaller increase in C-max (similar to 118%) compared with the normal group. Mean half-life (t(1/2)) values were prolonged in the moderate impairment group (21 hours) relative to the normal group (11 hours). There was a decrease in apparent clearance (CL/F) and an increase in AUC(infinity u) (AUC(infinity) x % drug unbound). The percentage of carisbamate unbound to proteins did not change across the groups, suggesting the increases in AUC(infinity) were due to decreased intrinsic hepatic clearance. Carisbamate 200 mg was well tolerated.