Abstracts

To evaluate the pharmacokinetics of a single dose of oxcarbazepine in healthy volunteers and subjects with mild and moderate hepatic impairment. Healthy volunteers and hepatically impaired subjects (45 to 65 years of age) were stratified using the Child-Pugh Impairment Classification System to one of the following groups: mild hepatic impairment, Child-Pugh Classification A; and moderate hepatic impairment, Child-Pugh Classification B. All subjects received a single dose of 900 mg of oxcarbazepine. Blood samples were collected pre-dose and at 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours post-dose for the determination of levels of the active monohydroxy derivative, MHD. The following PK parameters for MHD were determined using model independent methods: C[sub]max[/sub], t[sub]max[/sub], t[sub]1/2[/sub], AUC (0-96 h), and AUC (0-[infin]). An analysis of covariance (ANCOVA) model with baseline hepatic function as the covariate was used to determine the influence of any hepatic effects on MHD pharmacokinetics. A total of 26 subjects entered the study and samples were obtained from 19 subjects (healthy volunteers n=6; mild hepatic impairment n=7; moderate hepatic impairment n=6) for analysis. All three groups were well matched with respect to race and age. No major differences in baseline medical history/concomitant diagnosis data between the three groups were noted, except for expected liver function-related findings separating the Child-Pugh A and B groups. There were no statistically significant differences in any pharmacokinetic parameters, in particular C[sub]max[/sub] and AUC values, between the healthy volunteers and the subjects with mild or moderate hepatic impairment. None of the hepatically impaired subjects reported adverse events. Three healthy volunteers reported the following mild adverse events: dry mouth, dizziness, and somnolence. Decreased creatinine clearance was noted for one healthy volunteer 5 and 15 days post-dose (13% and 59% decrease, respectively). Creatinine clearance returned to normal by 21 and 30 days post-dose. This volunteer was asymptomatic throughout the study and no action was required. Mild and moderate hepatic impairment does not seem to affect plasma levels of MHD after a single dose of oxcarbazepine. The data presented suggest that oxcarbazepine doses may not have to be altered in subjects with mild to moderate hepatic impairment. (Supported by Novartis Pharmaceuticals)