Pharmacokinetics of reboxetine in volunteers with hepatic impairment

Objective: Reboxetine is a unique selective norepinephrine (noradrenaline) reuptake inhibitor (selective NRI) that is effective and well tolerated at a dosage of 8 to 10 mg/day in the short- and long-term treatment of depress ion. The objective of the study was to assess reboxetine pharmacokinetics i n patients with moderate to severe hepatic impairment. Design: 12 volunteers with alcoholic liver disease received a single 4mg do se of reboxetine, and plasma reboxetine concentrations were measured by hig h performance liquid chromatography. Results: Reboxetine was well tolerated by all recipients. Compared with the pharmacokinetics of reboxetine 4mg determined in a similar study in young healthy volunteers, maximum concentration (C-max) was up to 22% lower in pa tients with liver disease, the area under the plasma reboxetine concentrati on-time curve extrapolated to infinity (AUC(infinity)) was up to 92% higher , and the terminal elimination half-life (t1/2z) was up to 150% longer. Whe n comparing volunteers with moderate (Child-Pugh score 7 to 8) and severe h epatic (Child-Pugh score 10 to 13) impairment, mean Cmax was 21% lower, mea n AUG, was 10% greater and t1/2z was 23% longer in the severely impaired co mpared with the moderately impaired patients. Although none of these differ ences was statistically significant, the trend is of clinical relevance. Conclusions: The severity of alcoholic liver disease does not appear to aff ect reboxetine pharmacokinetics in a statistically significant manner, but there is a clinically relevant trend in changes to reboxetine pharmacokinet ics with increasing hepatic impairment. Although reboxetine 4mg was well to lerated in the present study, comparisons with historical data from young h ealthy volunteers suggest that a lower starting dosage of reboxetine (4 mg/ day in divided doses) should be used in patients with hepatic impairment.