title: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Titusville, NJ 08560, USA. tmoore17@its.jnj.com
authors.forename: Kenneth
authors.initials: K
authors.lastname: Moore
authors.forename: Peter
authors.initials: P
authors.lastname: Zannikos
authors.forename: Bhavna
authors.initials: B
authors.lastname: Solanki
authors.forename: Andrew
authors.initials: A
authors.lastname: Greenspan
authors.forename: Tom
authors.initials: T
authors.lastname: Verhaeghe
authors.forename: H Robert
authors.initials: HR
authors.lastname: Brashear
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D001711:Biotransformation; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D005858:Germany; D020719:Glucuronides / Q000652:urine; D006207:Half-Life; D006801:Humans; D016014:Linear Models; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011485:Protein Binding; D012720:Severity of Illness Index
chemical_list: D000700:Analgesics; D000927:Anticonvulsants; D002219:Carbamates; D020719:Glucuronides; C518914:S-2-O-carbamoyl-1-o-chlorophenyl-ethanol