Association study identifies genetic determinants and non-genetic factors on steady-state plasma and therapeutic outcome of galantamine in mixed dementia

Thitipon Yaowaluk; Vorapun Senanarong; Chanin Limwongse; Rasda Boonprasert; Duangkamon Bunditvorapoom; Supannee Kaewsutthi; Pornpimol Kijsanayotin

doi:10.1007/s00228-022-03322-1

Association study identifies genetic determinants and non-genetic factors on steady-state plasma and therapeutic outcome of galantamine in mixed dementia

Eur J Clin Pharmacol. 2022 Aug;78(8):1249-1259. doi: 10.1007/s00228-022-03322-1. Epub 2022 May 28.

Authors

Thitipon Yaowaluk¹, Vorapun Senanarong², Chanin Limwongse³, Rasda Boonprasert⁴, Duangkamon Bunditvorapoom³, Supannee Kaewsutthi⁵, Pornpimol Kijsanayotin⁶

Affiliations

¹ Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Phayathai Rd, Pathumwan, Bangkok, 10330, Thailand.
² Division of Neurology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
³ Division of Medical Genetics, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
⁴ Clinical Toxicology Laboratory, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
⁵ Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
⁶ Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Phayathai Rd, Pathumwan, Bangkok, 10330, Thailand. pornpimol.k@chula.ac.th.

PMID: 35633386
DOI: 10.1007/s00228-022-03322-1

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.

Keywords: CYP2D6; Galantamine; Mixed dementia; UGT1A1.

MeSH terms

Alzheimer Disease* / drug therapy
Apolipoproteins E / genetics
Cytochrome P-450 CYP2D6 / genetics
Cytochrome P-450 CYP3A / genetics
Galantamine* / therapeutic use
Genotype
Humans
Treatment Outcome

Substances

Apolipoproteins E
Galantamine
Cytochrome P-450 CYP2D6
Cytochrome P-450 CYP3A