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

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.

Keywords: CYP2D6; CYP3A; NR1I2; POR; donepezil; population pharmacokinetics.

Figure 1

Donepezil dose-normalized plasma concentration–time plots of male (black symbols) and female (white symbols) patients (circles represent extensive CP2D6 metabolizers; squares, poor metabolizers; triangles, ultrarapid metabolizers; star, the PM patient with very low drug concentration excluded from the final model parameters estimations). Simulations were performed for male patients, extensive CYP2D6 metabolizers and receiving 10 mg of donepezil per day (solid line represents average population prediction value; dashed lines, 95% prediction intervals)