AN EVALUATION OF THE PHARMACOKINETICS OF DONEPEZIL HCL IN PATIENTS WITH IMPAIRED HEPATIC-FUNCTION

Aim The aim of this study was to evaluate the pharmacokinetic profile of donepezil HCl (5 mg) in patients with impaired hepatic function, fo llowing the administration of single oral doses. Methods This was an o pen-label, non-randomized study comparing the pharmacokinetic profile of donepezil in male volunteers with chronic compensated cirrhosis of the liver (n = 10) to that in healthy age- and sex-matched controls (n = 10). Each subject received a single 5 mg oral dose of donepezil. Bl ood samples for pharmacokinetic analyses were taken at specified inter vals up to 120-h post-dose. Concentrations of donepezil in plasma were determined by HPLC with UV detection. Results No statistically signif icant differences in donepezil pharmacokinetics were observed bt tween hepatically impaired patients and normal subjects, with the exception of C-max. The hepatically impaired patients showed a statistically si gnificant, but not clinically significant, higher mean C-max value of 6.6 ng ml(-1) compared with the control group, which had a mean C-max value of 4.8 ng ml(-1) (P = 0.022). This represented an increase of 37 .5%. The observed changes in AUC values were smaller and not statistic ally different. The AUC((0-120)) and AUC((0-infinity)) were 7% and 21% larger in the hepatically impaired patients than ill the normal subje cts, respectively, although clearance and volume of distribution were almost identical in the two groups. The t(1/2) increased by 20%, but t his change was also not statistically significant. Donepezil was equal ly well tolerated by all subjects. Conclusions This study demonstrates that compromised hepatic function does not produce clinically signifi cant changes in the pharmacokinetics of donepezil following single-dos e administration. These results suggest that the administration of don epezil to patients with hepatic disease in clinical practice should no t require any dosing modifications.