Increased plasma donepezil concentration improves cognitive function in patients with dementia with Lewy bodies: An exploratory pharmacokinetic/pharmacodynamic analysis in a phase 3 randomized controlled trial.
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 10mg/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 10mg/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 5mg/day, increasing the dose to 10mg/day to increase plasma concentration is worthwhile to further improve cognitive function.
Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan. Electronic address: morie@med.tohoku.ac.jp.
Etsuro
E
Mori
Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, 5-1 Oe Chuo-ku, Kumamoto, Kumamoto 862-0973, Japan.
Manabu
M
Ikeda
Eisai Product Creation Systems, Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo 112-8088, Japan.
Kenya
K
Nakai
Eisai Product Creation Systems, Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo 112-8088, Japan.
Hideaki
H
Miyagishi
Eisai Product Creation Systems, Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo 112-8088, Japan.
Masaki
M
Nakagawa
Department of Psychiatry, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
Kenji
K
Kosaka
D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007189:Indans / Q000097:blood* / Q000627:therapeutic use; D020961:Lewy Body Disease / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000097:blood* / Q000627:therapeutic use; D010880:Piperidines / Q000097:blood* / Q000627:therapeutic use; D011674:Pulse; D012720:Severity of Illness Index; D016896:Treatment Outcome
D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil; D019389:Cytochrome P-450 CYP2D6
Clinical; Cognitive/behavioral; Dementia with Lewy bodies; Dementia/aging; Donepezil; Efficacy; Mini-Mental State Examination; Pharmacokinetis; Safety