Association study identifies genetic determinants and non-genetic factors on steady-state plasma and therapeutic outcome of galantamine in mixed dementia
Issued Date
2022-08-01
Resource Type
ISSN
00316970
eISSN
14321041
Scopus ID
2-s2.0-85131037074
Pubmed ID
35633386
Journal Title
European Journal of Clinical Pharmacology
Volume
78
Issue
8
Start Page
1249
End Page
1259
Rights Holder(s)
SCOPUS
Bibliographic Citation
European Journal of Clinical Pharmacology Vol.78 No.8 (2022) , 1249-1259
Suggested Citation
Yaowaluk T., Senanarong V., Limwongse C., Boonprasert R., Bunditvorapoom D., Kaewsutthi S., Kijsanayotin P. Association study identifies genetic determinants and non-genetic factors on steady-state plasma and therapeutic outcome of galantamine in mixed dementia. European Journal of Clinical Pharmacology Vol.78 No.8 (2022) , 1249-1259. 1259. doi:10.1007/s00228-022-03322-1 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/86842
Title
Association study identifies genetic determinants and non-genetic factors on steady-state plasma and therapeutic outcome of galantamine in mixed dementia
Author's Affiliation
Other Contributor(s)
Abstract
Purpose: This study aimed to evaluate the influence of genetic polymorphisms of drug-metabolizing enzyme genes, transporter gene, pathological gene (APOE), and non-genetic factors on therapeutic outcomes as well as steady-state plasma concentrations (Cpss) of galantamine in Thai patients with mixed dementia. Methods: Fifty-one Thai patients with mixed dementia who received galantamine for at least 6 months were recruited. CYP2D6, CYP3A5, and ABCB1 polymorphisms were detected by TaqMan® Genotyping Assay. UGT1A1 and APOE polymorphism was detected by direct Sanger sequencing technique and restriction fragment length polymorphism technique. Cpss of galantamine was measured by ultra-performance liquid chromatography. Associations of genetic and non-genetic factors with Cpss and clinical outcomes (change in cognitive function as measured by the Thai Mental State Examination (ΔTMSE) scores) were determined by using univariate and multivariate analysis. Results: The multivariate regression model revealed that patients who carried one or more detrimental allelic variant (CYP2D6, CYP3A5, and UGT1A1) showed a tendency toward a higher galantamine adjusted Cpss (B = 34.559, 95% CI = 0.741–68.377, p value = 0.045). Logistic regression analysis also revealed CYP2D6*10 carriers were significantly associated with higher ΔTMSE (B = 5.227, 95% CI = 2.395–8.060, p value = 0.001). UGT1A1 mutant alleles and non-genetic factors including concomitant use of statin drugs and higher education level can attenuate therapeutic outcomes of galantamine. Conclusion: Pharmacokinetic-related genes including CYP2D6*10 and UGT1A1 mutant alleles were significantly associated with galantamine adjusted Cpss and cognitive function. Determination of Cpss and genotype could be an adjunct examination to provide further explanation in interindividual variability of galantamine therapeutic outcome.