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

Abstract

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 (AUC(∞)) was observed for the mild impairment group compared with the normal group (ratio of geometric means ~116%), while mean maximum plasma concentration (C(max)) values were similar (ratio of geometric means ~94%). The AUC(∞) value for the moderate hepatic-impaired group was approximately 207% that of the normal group, while there was a smaller increase in C(max) (~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(∞u) (AUC(∞) × % drug unbound). The percentage of carisbamate unbound to proteins did not change across the groups, suggesting the increases in AUC(∞) were due to decreased intrinsic hepatic clearance. Carisbamate 200 mg was well tolerated.

Qualification and application of liquid chromatography-quadrupole time-of-flight mass spectrometric method for the determination of carisbamate in rat plasma and prediction of its human pharmacokinetics using physiologically based pharmacokinetic modeling

“…Carisbamate (S-2-O-carbamoyl-1-o-chlorophenyl-ethanol) is an investigational neuromodulatory agent, initially developed from SK Biopharmaceuticals (Seongnam, Korea) for antiepileptic treatment [ 1 2 3 4 5 6 ]. Although the exact mechanism of action for carisbamate is not known, carisbamate has been studied for the treatment of epilepsy, essential tremor and migraine [ 4 5 ].…”

“…Carisbamate (S-2-O-carbamoyl-1-o-chlorophenyl-ethanol) is an investigational neuromodulatory agent, initially developed from SK Biopharmaceuticals (Seongnam, Korea) for antiepileptic treatment [ 1 2 3 4 5 6 ]. Although the exact mechanism of action for carisbamate is not known, carisbamate has been studied for the treatment of epilepsy, essential tremor and migraine [ 4 5 ]. In phase I clinical trials to healthy subjects, carisbamate has shown linear pharmacokinetics at doses of 100 to 1,500 mg, high oral bioavailability (F) of > 95% and a low oral clearance (CL/F) of 3.4–4.2 L/h, equaling < 5% of liver blood flow [ 1 2 7 ].…”