Concurrent administration of donepezil HCl and ketoconazole: assessment of pharmacokinetic changes following single and multiple doses

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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.


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.


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 Cmax and AUC(0-24) of donepezil. The concurrent administration of both drugs resulted in a 12% greater Cmax (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 Cmax (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.


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.

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