Population pharmacokinetic approach to evaluate the effect of CYP2D6, CYP3A, ABCB1, POR and NR1I2 genotypes on donepezil clearance.

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State: Public
Version: author
Serval ID
serval:BIB_D0309E8CA034
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Population pharmacokinetic approach to evaluate the effect of CYP2D6, CYP3A, ABCB1, POR and NR1I2 genotypes on donepezil clearance.
Journal
British Journal of Clinical Pharmacology
Author(s)
Noetzli M., Guidi M., Ebbing K., Eyer S., Wilhelm L., Michon A., Thomazic V., Stancu I., Alnawaqil A.M., Bula C., Zumbach S., Gaillard M., Giannakopoulos P., von Gunten A., Csajka C., Eap C.B.
ISSN
1365-2125 (Electronic)
ISSN-L
0306-5251
Publication state
Published
Issued date
2014
Peer-reviewed
Oui
Volume
78
Number
1
Pages
135-144
Language
english
Notes
Publication types: Journal ArticlePublication Status: ppublish
Abstract
AIMS: A large interindividual variability in plasma concentrations has been reported in patients treated with donepezil, the most frequently prescribed antidementia drug. We aimed to evaluate clinical and genetic factors influencing donepezil disposition in a patient population recruited from a naturalistic setting.
METHODS: A population pharmacokinetic study was performed including data from 129 older patients treated with donepezil. The patients were genotyped for common polymorphisms in the metabolic enzymes CYP2D6 and CYP3A, in the electron transferring protein POR and the nuclear factor NR1I2 involved in CYP activity and expression, and in the drug transporter ABCB1.
RESULTS: The average donepezil clearance was 7.3 l h(-1) with a 30% interindividual variability. Gender markedly influenced donepezil clearance (P < 0.01). Functional alleles of CYP2D6 were identified as unique significant genetic covariate for donepezil clearance (P < 0.01), with poor metabolizers and ultrarapid metabolizers demonstrating, respectively, a 32% slower and a 67% faster donepezil elimination compared with extensive metabolizers.
CONCLUSION: The pharmacokinetic parameters of donepezil were well described by the developed population model. Functional alleles of CYP2D6 significantly contributed to the variability in donepezil disposition in the patient population and should be further investigated in the context of individual dose optimization to improve clinical outcome and tolerability of the treatment.
Pubmed
Web of science
Open Access
Yes
Create date
11/02/2014 14:40
Last modification date
20/08/2019 16:50
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