TY - JOUR
T1 - Increased plasma donepezil concentration improves cognitive function in patients with dementia with Lewy bodies
T2 - An exploratory pharmacokinetic/pharmacodynamic analysis in a phase 3 randomized controlled trial
AU - Mori, Etsuro
AU - Ikeda, Manabu
AU - Nakai, Kenya
AU - Miyagishi, Hideaki
AU - Nakagawa, Masaki
AU - Kosaka, Kenji
N1 - Publisher Copyright:
© 2016 The Authors.
PY - 2016/7/15
Y1 - 2016/7/15
N2 - Objective To investigate whether increasing plasma donepezil concentration further improves cognitive function and neuropsychiatric symptoms without compromising safety in patients with dementia with Lewy bodies (DLB). Methods We analyzed data from a 12-week phase 3 trial of donepezil (5 and 10 mg/day) in patients with DLB. The contribution of factors affecting plasma donepezil concentration was evaluated using multivariate regression analysis. The relationships between plasma donepezil concentration and efficacy (cognitive function as measured by the Mini-Mental State Examination [MMSE], hallucinations and cognitive fluctuation), or safety (blood pressure, pulse rate, body weight, and parkinsonism as measured by the Unified Parkinson's Disease Rating Scale part III) were assessed by scatterplots and Pearson correlation. Results The data of 87 patients were used in the analyses. Plasma donepezil concentration increased proportionally with increasing dose from 5 to 10 mg/day. The dose (contribution rate: 0.39, p < 0.0001) and age (contribution rate: 0.12, p = 0.0003) were statistically significant contributing factors affecting plasma donepezil concentration. Plasma donepezil concentration correlated significantly with improvement of MMSE score (p = 0.040), but no significant correlations were found with the change in other tested parameters. Conclusions Plasma donepezil concentration correlated positively with change in cognitive function without affecting safety, and was affected mainly by dose and to a lesser extent by age. Therefore, for patients in whom safety concerns are not found at donepezil 5 mg/day, increasing the dose to 10 mg/day to increase plasma concentration is worthwhile to further improve cognitive function.
AB - Objective To investigate whether increasing plasma donepezil concentration further improves cognitive function and neuropsychiatric symptoms without compromising safety in patients with dementia with Lewy bodies (DLB). Methods We analyzed data from a 12-week phase 3 trial of donepezil (5 and 10 mg/day) in patients with DLB. The contribution of factors affecting plasma donepezil concentration was evaluated using multivariate regression analysis. The relationships between plasma donepezil concentration and efficacy (cognitive function as measured by the Mini-Mental State Examination [MMSE], hallucinations and cognitive fluctuation), or safety (blood pressure, pulse rate, body weight, and parkinsonism as measured by the Unified Parkinson's Disease Rating Scale part III) were assessed by scatterplots and Pearson correlation. Results The data of 87 patients were used in the analyses. Plasma donepezil concentration increased proportionally with increasing dose from 5 to 10 mg/day. The dose (contribution rate: 0.39, p < 0.0001) and age (contribution rate: 0.12, p = 0.0003) were statistically significant contributing factors affecting plasma donepezil concentration. Plasma donepezil concentration correlated significantly with improvement of MMSE score (p = 0.040), but no significant correlations were found with the change in other tested parameters. Conclusions Plasma donepezil concentration correlated positively with change in cognitive function without affecting safety, and was affected mainly by dose and to a lesser extent by age. Therefore, for patients in whom safety concerns are not found at donepezil 5 mg/day, increasing the dose to 10 mg/day to increase plasma concentration is worthwhile to further improve cognitive function.
KW - Clinical
KW - Cognitive/behavioral
KW - Dementia with Lewy bodies
KW - Dementia/aging
KW - Donepezil
KW - Efficacy
KW - Mini-Mental State Examination
KW - Pharmacokinetis
KW - Safety
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U2 - 10.1016/j.jns.2016.05.001
DO - 10.1016/j.jns.2016.05.001
M3 - Article
C2 - 27288803
AN - SCOPUS:84970954404
VL - 366
SP - 184
EP - 190
JO - Journal of the Neurological Sciences
JF - Journal of the Neurological Sciences
SN - 0022-510X
ER -