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Population pharmacokinetic approach to evaluate the effect of CYP2D6 , CYP3A , ABCB1 , POR and NR1I2 genotypes on donepezil clearance
Author(s) -
Noetzli Muriel,
Guidi Monia,
Ebbing Karsten,
Eyer Stephan,
Wilhelm Laurence,
Michon Agnès,
Thomazic Valérie,
Stancu Ioana,
Alnawaqil AbdelMessieh,
Bula Christophe,
Zumbach Serge,
Gaillard Michel,
Giannakopoulos Panteleimon,
Gunten Armin,
Csajka Chantal,
Eap Chin B.
Publication year - 2014
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/bcp.12325
Subject(s) - population , medicine , environmental health
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.