Gene Polymorphisms Affecting the Pharmacokinetics and Pharmacodynamics of Donepezil Efficacy

Abstract

Donepezil (DNP) is the first-line drug used for Alzheimer's disease (AD). However, the therapeutic response rate of patients to DNP varies from 20 to 60%. The main reason for the large differences in the clinical efficacy of DNP therapy is genetic factors, some of which affect pharmacokinetics (PK), while others affect pharmacodynamics (PD). Thus, much emphasis has been placed on the investigation of an association between PK-and PD-related gene polymorphisms and therapeutic response to DNP, but a consistent view does not yet exist. In this review, we summarize recent findings regarding genetic factors influencing the clinical efficacy of DNP, including substantial differences in individual responses as a consequence of polymorphisms in Cytochrome P450 (CYP) 2D6, CY3A4, CY3A5, APOE, ABCA1, ABCB1, ESR1, BCHE, PON-1, CHRNA7, and CHAT. We also discuss possible strategies for the evaluation of the clinical efficacy of DNP, with a specific focus on possible biomarkers of PK/PD parameters, and provide perspectives and limitations within the field, which will also be beneficial for understanding the multiple mechanisms of DNP therapy in AD.

Pharmacogenetics of Donepezil and Memantine in Healthy Subjects

“…The reason why we did not find a significant association with them in the multivariate analysis may be due to the limited number of subjects included in the study and the reduced number of volunteers with a UM or a PM phenotype within our dataset. We did not find an association between rs4646438, rs35599367, and rs55785340 ( CYP3A4 ) and pharmacokinetics in accordance with previous publications [ 14 , 24 ]. Moreover, we found an association between donepezil AUC, C max , and T max , and rs6280 ( DRD3 ) in the multivariate analysis, but they did not reach the significance threshold.…”

“…The SNP rs1803274 ( BCHE ), located on the butyrylcholinesterase gene was associated with donepezil response, although the results are controversial [ 19 , 45 ]. Finally, the APOE ε4/E4 genotype, associated with the greatest AD risk, appears to be associated with the worst response to drugs [ 24 ]. The reason why these genes were not included in the present study is that we focused on genes involved in donepezil and memantine pharmacokinetics.…”

“…The lack of efficacy of these drugs may be partially explained by genetic reasons [ 17 ]. Therefore, several pharmacogenetic studies searching for biomarkers of donepezil response have been performed so far [ 12 , 14 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. There is an annotation in donepezil’s label that informs that CYP2D6 poor metabolizers had a 31.5% slower clearance than normal metabolizers [ 25 ].…”

Paraoxonase Role in Human Neurodegenerative Diseases

“…Several factors are able to change the therapeutic response to acetylcholinesterase inhibitors. However, association studies of PON1 enzymatic activity and polymorphisms with environmental exposure, eating habits, genetic factors of susceptibility to AD, drug metabolism-associated polymorphism, are lacking [ 209 , 210 , 211 ].…”

Induced pluripotent stem cell-based organ-on-a-chip as personalized drug screening tools: A focus on neurodegenerative disorders

“…For example, the clinical efficacy of the first approved drug in AD treatment, donepezil, is highly variable between patients and its efficacy is strongly influenced by several genetic factors, as cytochrome P450 polymorphism. 13 …”