Association of genetic and non-genetic factors with clinical responses of donepezil and Galantamine in Thai patients with dementia

Abstract

Donepezil and galantamine are commonly prescribed for the treatment of dementia. However, the response rate of acetylcholinesterase inhibitors is only 15-35 %. Inter-individual variability in donepezil and galantamine response has been associated with genetic factor in some population. Moreover, non-genetic factors such as age, gender, education level, comorbidities and drug-drug interactions can influence pharmacokinetic profiles and drug responses. Therefore, this study aims to investigate the association of genetic variations that involved therapeutic effects of donepezil and galantamine including pathogenic gene; APOE, drug metabolizing genes; CYP2D6, CYP3A5, UGT1A1, transporter gene; ABCB1 and non-genetic factors with therapeutic outcomes as measured as Thai Mental State Examination (TMSE) scores and steady-state plasma concentrations (Cpss) of donepezil and galantamine in Thai patients with firstly diagnosed dementia. 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) and a better clinical outcomes of donepezil i.e. ΔTMSE (p-value = 0.023 and B = 4.107, p-value = 0.002), especially in patients with Alzheimer’s disease (AD). Concomitant use of memantine was found to be associated with increased Cpss of donepezil. Whereas, co-medication with antidepressant drugs attenuated clinical responses of donepezil in patients with AD. Age was found to be negative associated with donepezil response in vascular dementia patients. For galantamine, the multivariate regression model revealed that patients with mixed dementia who carried a more detrimental allelic variants in combined CYP2D6, CYP3A5, and UGT1A1 were associated with higher galantamine’s adjusted Cpss (B = 34.559, p-value = 0.045). Both multiple linear and logistic regression analysis consistently revealed that CYP2D6*10 carriers was significantly associated with higher ΔTMSE (B = 5.227, p-value = 0.001). UGT1A1 mutant alleles and non-genetic factors including concomitant use of statin drugs and higher education level may attenuate the therapeutic outcome of galantamine. The present findings highlight the possibility of using genetic testing to guide personalized dementia therapy with donepezil and galantamine in the forthcoming precision medicine era.