AIMSA 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. METHODSA 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. RESULTSThe 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. CONCLUSIONThe 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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The pharmacokinetics of donepezil have been previously investigated, examining the influence of a limited number of genetic factors.• Non-published population PK analysis in files submitted for drug registration indicate that, compared with the CYP2D6 extensive metabolizers, poor metabolizers had a 32% slower clearance and ultrarapid metabolizers had 24% faster clearance.• The recommended daily dose of donepezil is between 5 to 10 mg. WHAT THIS STUDY ADDS• To our knowledge, this is the most extensive study examining the influence of genetic factors other than CYP2D6 (also including NR1/2 and POR) on donepezil pharmacokinetics.• Model-based simulations show that, when compared with the suggested therapeutic range of 30-75 ng ml −1 , while considering the interindividual variability in CL, for a 10 mg daily regimen CYP2D6 ultrarapid metabolizers are not expected to exceed the 75 ng ml −1 upper limit, whereas it is expected that 43% and 6% of PMs and EMs, respectively, would present average concentrations beyond this threshold.

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