Premium
Steady‐state pharmacokinetics, pharmacodynamics and tolerability of donepezil hydrochloride in hepatically impaired patients
Author(s) -
Reyes Josephine F.,
Vargas Ramon,
Kumar Dinesh,
Cullen Edward I.,
Perdomo Carlos A.,
Pratt Raymond D.
Publication year - 2004
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 - 10.1111/j.1365-2125.2004.01802.x
Subject(s) - tolerability , pharmacokinetics , pharmacodynamics , medicine , donepezil , cmax , pharmacology , gastroenterology , adverse effect , dementia , disease
Aims To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of donepezil HCl 5 mg following oral doses for 1 and 24 days in hepatically impaired patients compared with healthy controls under steady‐state, multiple‐dose conditions. Methods In this single‐centre, multiple‐dose, open‐label study, patients with impaired hepatic function (Child–Pugh grade A or B) and healthy controls (matched by gender, age and weight to the hepatically impaired patients) received a single 5 mg dose of donepezil on day 1 and then donepezil HCl 5 mg once daily from days 6 to 29. PK and PD (determination of erythrocyte acetylcholinesterase inhibition) parameters were evaluated on days 1 and 29. Treatment‐emergent adverse events (AEs), vital signs, physical examination and clinical laboratory test parameters were monitored throughout the study. Results A total of 35 subjects (18 patients with hepatic impairment and 17 healthy controls) were enrolled and 32 subjects (16 in each group) completed the study. On day 1 (following a single dose) hepatically impaired patients showed a significant decrease in T max , while t ½ and AUC 0–∞ were significantly increased compared with the healthy controls. On day 29 (following multiple doses), AUC 0−24 h , C max , t ½ , C SS , and R A were significantly increased in hepatically impaired patients compared with healthy controls. AUC 0−24 h increased by 47.6% in the patients with hepatic impairment compared with the healthy controls. There were no significant differences in PD between the groups, although at steady state, the mean AChE inhibition was 16.2% higher in the hepatically impaired patients. No serious AEs were reported and no subject withdrew from the study due to AEs. The most common AEs in both groups were headache and diarrhoea. No clinically significant changes from baseline were observed in vital signs, physical examination findings or electrocardiograms. There was a significant difference in the number of hepatically impaired subjects with abnormalities in serum glucose compared with healthy subjects. However, these elevations were not associated with AEs. Conclusions The results of this study suggest that patients with AD and mild to moderate hepatic impairment (Child–Pugh grade A or B) can be safely given donepezil 5 mg once daily and that this dose is associated with a nonsignificantly higher AChE inhibition than age‐matched volunteers.