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The effect of multiple doses of donepezil HCl on the pharmacokinetic and pharmacodynamic profile of warfarin
Author(s) -
Paul J. Tiseo,
Karen Foley,
Lawrence Friedhoff
Publication year - 1998
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1998.0460s1045.x
Subject(s) - pharmacokinetics , warfarin , pharmacodynamics , crossover study , prothrombin time , medicine , pharmacology , area under the curve , donepezil , anesthesia , atrial fibrillation , placebo , dementia , alternative medicine , pathology , disease
Aim The aim of the study was to examine the pharmacokinetic and pharmacodynamic profiles of single doses of warfarin (25 mg) following administration alone, and in combination with multiple doses of donepezil HCl (10 mg day −1 ) in healthy volunteers.Methods This was an open‐label, two‐period crossover study in 12 healthy male volunteers, aged 18–55 years, who were randomized to one of the following treatment groups: (A) donepezil administered for 19 consecutive days with a single dose of warfarin administered on day 14. On day 20, there was a 21‐day washout period after which a single dose of warfarin was again administered, and (B) an initial 13‐day period with no medication, then a single dose of warfarin administered alone on day 14, followed by a 14‐day washout period. Donepezil was then administered for 19 days (to day 47), with an additional single dose of warfarin administered on day 41. Serial blood samples were collected over 144 h following both warfarin administrations in each treatment group. Pharmacokinetic parameters were assessed for both (R )‐ and (S )‐warfarin concentrations in plasma, and pharmacodynamic analyses utilizing prothrombin time were undertaken. Warfarin concentrations in plasma were determined by HPLC with fluorescence detection. The pharmacokinetic parameters C max , AUC (0–∞) , CL T /F, V λz /F and t ½ of both (R )‐ and (S )‐warfarin, maximum prothrombin time (R max ) and the area under the prothrombin–time curve (AUC PT ), were compared in the presence and absence of donepezil by analysis of variance (ANOVA ).Results No statistically significant differences in (R )‐ or (S )‐warfarin pharmacokinetics were observed when warfarin administered alone was compared to warfarin administered concurrently with donepezil. Warfarin pharmacodynamic parameters, R max and AUC PT , were also unchanged by concomitant administration of donepezil. No clinically significant changes in vital signs, ECG parameters or clinical laboratory tests were observed.Conclusions Concurrent administration of donepezil HCl does not alter the pharmacokinetic or pharmacodynamic profile of single doses of warfarin in healthy volunteers. These findings suggest that donepezil may be safely co‐administered with warfarin without the need for dose modification.