Influence of CYP2D6, CYP3A5, ABCB1, APOE polymorphisms and nongenetic factors on donepezil treatment in patients with Alzheimer’s disease and vascular dementia

Abstract

Purpose

This study aims to evaluate the influence of genetic polymorphisms of CYP2D6, CYP3A5, ABCB1, and APOE genes and nongenetic factors on steady-state plasma concentrations (Cpss) of donepezil and therapeutic outcomes in Thai patients with Alzheimer’s disease (AD) and vascular dementia (VAD).

Patients and methods

Eighty-five dementia patients who received donepezil for at least six months were recruited. CYP2D6, CYP3A5, ABCB1, and APOE polymorphisms were genotyped. Cpss of donepezil was measured. Association of genetic and non-genetic factors with Cpss and clinical outcomes of donepezil (cognitive function as measured by the Thai Mental State Examination score; TMSE) were determined by using univariate and multivariate analysis.

Results

Both univariate and multiple linear regression analysis indicated that only CYP2D6*10 allele was associated with higher Cpss (p-value =0.029 and B =0.478, p-value =0.032, respectively) that might influence the clinical outcomes of donepezil. ie, TMSE (p-value =0.010 and B =4.527, p-value =0.001) and ΔTMSE (p-value =0.023 and B =4.107, p-value =0.002), especially in patients with AD. Interestingly, concomitant use of memantine was found to be associated with increased Cpss of donepezil (p-value =0.007 and B =0.511, p-value =0.014). Whereas, co-medication with antidepressant drugs attenuated clinical responses in patients with AD (TMSE: B =−2.719, p-value =0.013 and ΔTMSE: B =−2.348, p-value =0.028). Age was a significant predictor of donepezil response in VAD patients. No significant association of CYP3A5*3, ABCB1 3435C>T or ABCB1 1236C>T, and APOE ε4 genotypes with Cpss or clinical outcomes of donepezil was found in this study.

Conclusion

Our results suggests that CYP2D6*10 strongly influences Cpss and there is a trend toward better outcomes of donepezil in patients with AD. Nongenetic factors including concomitant drugs treatment might alter Cpss of donepezil or clinical outcomes.

Keywords:

• donepezil
• CYP2D6 polymorphisms
• concomitant drugs treatment
• Alzheimer’s disease
• vascular dementia

Supplementary materials

Table S1 Cpss of donepezil and TMSE score in association with CYP2D6, CYP3A5, ABCB1, and APOE genotypes at the 10 mg maintenance dose

Table S2 Association of non-genetic factor and TMSE score of donepezil at 10-mg maintenance dose

Table S3 Bivariate analysis: Association of non-genetic continuous variable and TMSE score

Acknowledgments

This work was supported by the 90^th Anniversary of Chulalongkorn University Fund (GCUGR1125613040D), Chulalongkorn University. The authors would like to thank Assoc. Prof. Chulathida Chomchai, MD, Dean of International College Mahidol University and Assist. Prof. Charoen Treesak, Department of Clinical Pharmacy, Faculty of Pharmacy, Srinakharinwirot University, for constructive comments and manuscript revision as well as Assist. Prof. Chulaluk Komoltri, Department of Health Research and Development, Siriraj Hospital, Mahidol University, for statistical consultation. Finally, we are grateful to all patients for participating in this study.

Author contributions

All authors contributed toward data analysis, drafting and revising the paper, gave final approval of the version to be published and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest with respect to this work.