PMID- 15496218
OWN - NLM
STAT- MEDLINE
DCOM- 20050202
LR  - 20181130
IS  - 0306-5251 (Print)
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Linking)
VI  - 58 Suppl 1
IP  - Suppl 1
DP  - 2004 Nov
TI  - Steady-state pharmacokinetics, pharmacodynamics and tolerability of donepezil 
      hydrochloride in hepatically impaired patients.
PG  - 9-17
AB  - 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((1/2)) and AUC(0-infinity) were 
      significantly increased compared with the healthy controls. On day 29 (following 
      multiple doses), AUC(0-24 h), C(max), t((1/2)), 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.
FAU - Reyes, Josephine F
AU  - Reyes JF
AD  - Clinical Pharmacology, Eisai Medical Research Inc., Rigefield Park, NJ 07660, 
      USA. jo_reyes@eisai.com
FAU - Vargas, Ramon
AU  - Vargas R
FAU - Kumar, Dinesh
AU  - Kumar D
FAU - Cullen, Edward I
AU  - Cullen EI
FAU - Perdomo, Carlos A
AU  - Perdomo CA
FAU - Pratt, Raymond D
AU  - Pratt RD
LA  - eng
PT  - Clinical Trial
PT  - Controlled Clinical Trial
PT  - Journal Article
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Cholinesterase Inhibitors)
RN  - 0 (Indans)
RN  - 0 (Piperidines)
RN  - 8SSC91326P (Donepezil)
SB  - IM
MH  - Administration, Oral
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Cholinesterase Inhibitors/administration & dosage/*pharmacokinetics/pharmacology
MH  - Donepezil
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Indans/adverse effects/*pharmacokinetics/pharmacology
MH  - Liver Diseases/*metabolism
MH  - Male
MH  - Middle Aged
MH  - Piperidines/adverse effects/*pharmacokinetics/pharmacology
PMC - PMC1884555
EDAT- 2004/10/22 09:00
MHDA- 2005/02/03 09:00
PMCR- 2005/05/01
CRDT- 2004/10/22 09:00
PHST- 2004/10/22 09:00 [pubmed]
PHST- 2005/02/03 09:00 [medline]
PHST- 2004/10/22 09:00 [entrez]
PHST- 2005/05/01 00:00 [pmc-release]
AID - BCP1802 [pii]
AID - 10.1111/j.1365-2125.2004.01802.x [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2004 Nov;58 Suppl 1(Suppl 1):9-17. doi: 
      10.1111/j.1365-2125.2004.01802.x.