Aim The aim of this study was to characterize the pharmacokinetic and pharmacodynamic profile of donepezil HCl, a chemically distinct and specific acetylcholinesterase (AChE) inhibitor for the treatment of Alzheimer's disease, following administration of single oral doses. Methods This was a double-blind, randomized, single-dose, placebo-controlled, sequential-group, ascending-dose study in healthy male volunteers (n=48). Six dose levels were investigated, ranging from 0.3 to 6.0 mg. Donepezil concentrations in plasma were determined by HPLC with UV detection. Pharmacodynamic activity was determined by the radioenzymatic measurement of erythrocyte membrane acetylcholinesterase (rbc-AChE) inhibition. Results The pharmacokinetic disposition of donepezil was observed to be both linear and dose proportional following single-dose administration. The mean peak plasma concentration (C max ) of donepezil was observed at 4.1±1.5 h. The mean terminal disposition half-life was 81.5±22.0 h. The post-absorption phase of the plasma concentration-time curves for the 4.0 mg and 6.0 mg doses appeared to be biphasic, but the rate of donepezil clearance was independent of dose. Plasma concentrations for the 0.3, 0.6 and 0.9 mg dose groups were generally below the level of HPLC detection (2.0 ng ml −1 ), preventing accurate characterization of these doses.A direct correlation was observed between plasma donepezil concentrations and extent of AChE inhibition. For the 4.0 and 6.0 mg donepezil dose groups, maximal AChE inhibition ( E max ) ranged from 33% to 35% and there was significant correlation between AChE inhibition and donepezil plasma concentration ( P<0.005). Conclusions The pharmacokinetics of donepezil were found to be linear and dose proportional following the administration of single doses to healthy volunteers. A direct correlation was also observed between plasma donepezil concentrations and AChE inhibition. The extended half-life of donepezil makes it suitable for oncedaily dosing.

Aim The aim of this study was to examine the pharmacokinetics of donepezil HCl and ketoconazole separately, and in combination, following administration of single and multiple oral doses. Methods This was an open-label, randomized, three-period crossover study in healthy volunteers (n=21). During each treatment period, subjects received single daily doses of either donepezil HCl (5 mg ), ketoconazole (200 mg), or a combination of both drugs for 7 consecutive days. Pharmacokinetic comparisons were made between treatment groups for the day 1 and day 7 profiles. Each treatment period was followed by a 3-week, drug-free washout period. Results On both day 1 and day 7, a statistically significant difference was observed between the donepezil and the donepezil+ketoconazole treatment groups in terms of C max and AUC (0-24) of donepezil. The concurrent administration of both drugs resulted in a 12% greater C max (9.5 ng ml −1 versus 8.4 ng ml −1 ; P=0.01) and a 12% greater AUC (0-24) (135.2 ng h ml −1 versus 118.7 ng h ml −1 ; P=0.001) than donepezil alone on day 1, and a 26.8% greater C max (37.7 ng ml −1 versus 27.6 ng ml −1 ; P<0.0001) and a 26.4% greater AUC (0-24) (680.9 ng h ml −1 versus 501.0 ng h ml −1 ; P<0.0001) than donepezil alone on day 7.In contrast, ketoconazole plasma concentrations were unaffected by the concurrent administration of donepezil, and there were no statistically significant differences in ketoconazole pharmacokinetics when ketoconazole administered alone was compared with ketoconazole administered with donepezil. Conclusions The concurrent administration of ketoconazole and donepezil produces no change in ketoconazole plasma concentrations, but a statistically significant change in donepezil plasma concentrations. These observed changes, which are smaller than those produced by ketoconazole for other agents sharing the CYP-3A4 pathway, are most likely the result of donepezil also being metabolized by CYP-2D6, as well as its slow rate of clearance from plasma.

Aim The aim of the study was to evaluate the pharmacokinetics of theophylline administered alone, and in combination with donepezil HCl, following multiple‐dose administration of both drugs in healthy volunteers. Methods This was an open‐label, randomized, two‐period crossover study in healthy male volunteers (n=12). During each treatment period, subjects received either titrated‐dose theophylline alone, or in combination with donepezil (5 mg, once daily) for 10 consecutive days. On day 10 of each treatment period, serial blood samples for the determination of theophylline concentrations in plasma were measured up to 24 h. Treatment periods were separated by a 3‐week, drug‐free washout. Plasma concentrations of theophylline were determined by HPLC with UV detection. Results No statistically significant differences in theophylline pharmacokinetics (Cmax, AUC or tmax ) were observed between theophylline administered alone and in combination with donepezil. No clinically significant changes in vital signs, ECG parameters or clinical laboratory tests were observed in any subject during any treatment period. Conclusions Concurrent administration of donepezil HCl does not alter the pharmacokinetic profile of theophylline following multiple‐dose administration of both drugs in healthy volunteers. These findings suggest that donepezil may be safely co‐administered with theophylline without a need for dose modification or additional monitoring procedures.