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 depression. The objective of the study was to assess reboxetine pharmacokinetics in patients with moderate to severe hepatic impairment. Design: 12 volunteers with alcoholic liver disease received a single 4mg dose of reboxetine, and plasma reboxetine concentrations were measured by high 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 patients with liver disease, the area under the plasma reboxetine concentration-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. When comparing volunteers with moderate (Child-Pugh score 7 to 8) and severe hepatic (Child-Pugh score 10 to 13) impairment, mean Cmax was 21% lower, mean AUG, was 10% greater and t1/2z was 23% longer in the severely impaired compared with the moderately impaired patients. Although none of these differences was statistically significant, the trend is of clinical relevance. Conclusions: The severity of alcoholic liver disease does not appear to affect reboxetine pharmacokinetics in a statistically significant manner, but there is a clinically relevant trend in changes to reboxetine pharmacokinetics with increasing hepatic impairment. Although reboxetine 4mg was well tolerated in the present study, comparisons with historical data from young healthy volunteers suggest that a lower starting dosage of reboxetine (4 mg/day in divided doses) should be used in patients with hepatic impairment.