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

Abstract

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.

Comparison of Metabolism of Donepezil in Rat, Mini-Pig and Human, Following Oral and Transdermal Administration, and in an In Vitro Model of Human Epidermis

“…This comparison serves as a model for the future development of reformulated products by the dermal route. M2 [13]. Two of the metabolites, M1 and M2 are further conjugated to form M11 and M12.…”

The Effects of Donepezil in Alzheimer’s Disease – Results from a Multinational Trial¹

“…In addition, no clinically significant drug-drug interactions were observed, even though over 80% of the patients in these trials were taking one or more concomitant medications. Importantly, the cytochrome P450 isoenzyme inhibitors cimetidine [13] and ketoconazole [14] produce no clinically significant changes in the pharmacokinetics of donepezil, suggesting that dose modification is not necessary when donepezil is co-administered with such compounds.…”

Clinical Profile of Donepezil in the Treatment of Alzheimer’s Disease

“…As the pharmacokinetics of donepezil following single-dose administration are not altered to any clinically significant extent in patients with moderate to severely impaired renal [53] or compromised hepatic function [54], donepezil can be administered without dose adjustment in these patients. Furthermore, the pharmacokinetic profiles of donepezil are not altered to any clinically relevant extent when coadministered with several drugs including digoxin [55] and the P 450 inhibitors, cimetidine [56] and ketaconazole [57,58]. In addition, the pharmacokinetic and pharmacodynamic profiles of warfarin [59], theophylline [60], digoxin, cimetidine and ketoconazole are not altered by the concurrent administration of donepezil.…”