Pharmacokinetic and pharmacodynamic profile of donepezil HCl following single oral doses

Abstract

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.

Bioequivalence study of Donepezil hydrochloride in healthy Korean volunteers

“…Considering that the terminal half-life is 50-70 h, as shown here and in the previous study, the washout period of 4 weeks used in the present study is 10-fold higher than the half-life of donepezil and is sufficient to eliminate the first dose of the drug completely prior to the second administration. [3] Furthermore, for 13 subjects, the donepezil concentrations measured just prior to the second dose were below the LLOQ and for the other subjects, the values ranged from 0.11 to 0.24 ng/mL, which are less than 1% of the C max concentration. Thus, a washout period of 4 weeks is sufficient to ensure that the drug is eliminated and there is no carry-over effect in the second phase of the study Safety.…”

“…The observed pharmacokinetic values are consistent with previously reported donepezil PK data. [3] Orally administered donepezil (10 mg) was well tolerated. Of 32 participants who received the drug, AEs were reported in only two subjects, one after receiving the test compound and the other after receiving the reference compound .…”

“…In one study, the concentration of donepezil peaked (C max ) to 4.1±1.5 h after dosing and the mean terminal half-life was found to be 81.5±22.0 h. [3] The pharmacokinetics (PK) of donepezil were found to be linear and showed dose proportionality after the administration of single doses to healthy volunteers. [3] The elimination half-life of donepezil is about 70 h and the mean apparent plasma clearance (CL/F) is 0.13-0.19 L/h/kg.…”

“…[3] The elimination half-life of donepezil is about 70 h and the mean apparent plasma clearance (CL/F) is 0.13-0.19 L/h/kg. Donepezil is slowly absorbed from the gastrointestinal tract.…”

Donepezil for Alzheimer's Disease: Pharmacodynamic, Pharmacokinetic, and Clinical Profiles

“…After oral administration of donepezil, the maximal plasma concentration of the drug is reached at 2.4 to 4.4 h (47,51,62,89). The absorption of donepezil is not affected by food and does not vary with the time of the day (47).…”