Donepezil

Pharmacokinetics
The volume of distribution of donepezil is as high as 12-16 L/Kg. Over the range of weights from 50 kg to 110 kg, clearance of donepezil increased from 7.77 L/hr to 14.04 L/hr, with a value of 10 L/hr for 70-kg individuals. Population PK analysis revealed that, compared to the extensive metabolizes (EMs) of CYP2D6, poor metabolizes (PMs) had a 31.5% lower clearance and ultra-metabolizes (UMs) had a 24% higher clearance; donepezil clearance was reduced by 17% in patients receiving concomitant CYP2D6 inhibitors compared to patients taking donepezil alone.

Food has no significant effect on the pharmacokinetics of donepezil.

The median of steady-state plasma concentration for 10 mg immediate-release form and 23 mg sustained-release form are around 57 ng/mL and 120 ng/mL.

Caution is needed for concomitant use of donepezil and strong CYP3A4 inhibitors (e.g., ketoconazole) in CYP2D6 PMs. CYP2D6 and CYP3A4 are primarily liable for donepezil metabolism. Donepezil is a weak inhibitor of CYP2D6 and CYP3A4. Donepezil clearance was reduced with co-administration of strong or moderate CYP2D6 inhibitors such as bupropion, fluoxetine, paroxetine, quinidine, or duloxetine, terbinafine, respectively.

Consumption of a large amount of alcohol reduces donepezil in plasma concentration. According to the labeling of Aricept®, formal pharmacokinetic studies evaluated the potential of donepezil for interaction with theophylline, cimetidine, warfarin, digoxin, and ketoconazole. No effects of donepezil on the pharmacokinetics of these drugs were observed.

Cmax for 23 mg sustained-released form and 10 mg immediate-released form were 8.29 (ng/mL) and 19.8 (ng/mL), respectively. AUC0-inf for 23 mg sustained-released form and 10 mg immediate-released form were 565.65 (ng*h/mL) and 710.95 (ng*h/mL), respectively.

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