Clinical Response to Donepezil in Mild and Moderate Dementia: Relationship to Drug Plasma Concentration and CYP2D6 and APOE Genetic Polymorphisms

Miranda, Luís Felipe José Ravic de; Gomes, Karina Braga; Tito, Pedro Augusto Lopes; Silveira, Josianne Nicácio; Pianetti, Gérson Antônio; Byrro, Ricardo Martins Duarte; Peles, Patrícia Regina Henrique; Pereira, Fernando Henrique; Santos, Thiago Rezende dos; Assini, Arthur G.; Ribeiro, Valéria V.; Moraes, Edgar Nunes de; Caramelli, Paulo

doi:10.3233/jad-160164

Cited by 20 publications

(32 citation statements)

References 35 publications

(42 reference statements)

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“…CYP2D6 and CYP3A4 activities were measured using probe drugs but no direct genotyping was performed. 30 Based on the above conflicting reports, 24,25,27,[29][30][31]33 the current study was selectively conducted in dementia participants with the same degree of disease severity with no other major co-morbidities aiming to substantiate the effects of CYP2D6 genetic variation on drug dose and plasma levels. We demonstrated the relationships between genotypepredicted phenotype with donepezil dose and plasma concentrations in the univariate analysis.…”

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confidence: 99%

CYP2D6 Predicts Plasma Donepezil Concentrations in a Cohort of Thai Patients with Mild to Moderate Dementia

Chamnanphon¹,

Wainipitapong²,

Wiwattarangkul³

et al. 2020

PGPM

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Purpose: Donepezil, a drug frequently used to treat dementia, is mainly metabolized by cytochrome P450 2D6 (CYP2D6). This study investigated the relationships between CYP2D6 genotype and activity scores as well as predicted phenotype of plasma donepezil concentrations in 86 Thai dementia participants. Materials and Methods: CYP2D6 was genotyped using bead-chip technology (Luminex xTAG ® v.3). Steady-state trough plasma donepezil concentrations were measured using highperformance liquid chromatography. Results: Sixteen genotypes were found but the most frequent genotypes detected among our participants were CYP2D6*10/*10 (27.9%) and *1/*10 (26.7%). One-third of the participants had an activity score of 1.25 which predicted that they were normal metabolizers. The overall median (interquartile range) of plasma donepezil concentration was 51.20 (32.59-87.24) ng/mL. Normal metabolizers (NMs) had lower plasma donepezil concentrations compared to intermediate metabolizers (IMs) (41.15 (28.44-67.65) ng/mL vs 61.95 (35.25-97.00) ng/mL). Multivariate analysis showed that CYP2D6 activity score (r 2 = 0.50) and the predicted phenotype (independent of dose) could predict the plasma donepezil concentration (r 2 = 0.49). Conclusion: Plasma donepezil concentration in NMs was lower compared to IMs. Additional studies with larger sample size and use of next-generation sequencing as well as its outcomes are warranted to confirm the benefit of using pharmacogenetic-guided treatment for donepezil.

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confidence: 99%

CYP2D6 Predicts Plasma Donepezil Concentrations in a Cohort of Thai Patients with Mild to Moderate Dementia

Chamnanphon¹,

Wainipitapong²,

Wiwattarangkul³

et al. 2020

PGPM

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“…L. Miranda F и соавт. [19] обследовали 42 пациента с БА. Хороший клинический эффект от приема 10 мг донепезила (снижение по шкале MMSE не более чем на 1 балл за 12 мес) коррелировал с более высокой концентрацией препарата в плазме крови, но не с полиморфизмом CYP2D6.…”

Section: Discussionunclassified

Is it personalized treatment of dementia based on the CYP2D6 gene polymorphism possible?

Chebotareva

Левин

Markov

et al. 2018

Z. nevrol. psikhiatr. im. S.S. Korsakova

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Лечение деменции является одной из актуальных проблем современной неврологии. Применяемые в клинической практике антидементные препараты в части случаев оказываются неэффективными либо вызывают неприемлемые нежелательные явления. В рамках концепции персонализированного подхода к терапии ведется активный поиск предикторов эффективности и безопасности лечения у конкретного больного. Примерно 15-20% пациентам с болезнью Альцгеймера (БА) в силу особенностей фармакогенетики требуется применение ингибиторов холинэстеразы в дозах препарата, отличающихся от указанных в инструкции. Одна часть таких больных

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“…However, studies investigating this association have shown inconsistent results. [6][7][8][9][10][11][12][13][14] Blood concentration, in turn, might depend on the way the substance is metabolized. Whereas rivastigmine is mainly hydrolyzed and the inactive metabolite renally excreted, 15 donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 in the liver and undergoes glucuronidation.…”

Section: Introductionmentioning

confidence: 99%

“…25 Other factors influencing donepezil or rivastigmine blood concentrations have been described, such as sex, 20 age, [26][27][28] weight, 15,25 daily dose, 26 and duration of treatment. 11 Despite high clinical relevance, only a few studies have investigated the association between CYP2D6 polymorphism, donepezil plasma concentrations, and clinical efficacy of donepezil. While most studies did not find a statistically significant correlation between allele frequency and donepezil concentration or clinical outcome, 10,11,14,29 a few did.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Drug Monitoring of Rivastigmine and Donepezil Under Consideration of CYP2D6 Genotype-Dependent Metabolism of Donepezil

Ortner

Stange

Schneider

et al. 2020

DDDT

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Background: The efficacy of acetylcholinesterase inhibitors (AChE-I) might depend on blood concentration. While rivastigmine metabolism is independent of the cytochrome P450 system, its isoenzymes, especially CYP2D6, metabolize donepezil. CYP2D6 polymorphisms can cause altered enzyme activity resulting in lower or higher than expected drug concentrations of donepezil. Objective: We investigated correlations between clinical efficacy and serum concentrations of rivastigmine and donepezil under special consideration of CYP2D6 genotype or gene dose-dependent metabolism of donepezil. Methods: Serum concentrations of donepezil and rivastigmine were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Real-time quantitative polymerase chain reaction (PCR) and allele-specific PCR were performed to assess CYP2D6 genotype and gene dose. Results: Patients treated with rivastigmine (n=28) or donepezil (n=48) were included in the study. Both gene dose and metabolism type significantly predicted the level of donepezil serum concentration (p=0.019 and p=0.013, respectively). In the rivastigmine group, changes of the word list delayed recall subtest before treatment and under stable medication were significantly associated with rivastigmine serum levels (β=0.465; p=0.018). Drug serum concentrations were outside the recommended range in a substantial percentage of participants, which might have contributed to poor correlations between changes in cognitive measures and drug concentrations. Donepezil serum concentrations significantly depended on CYP2D6 gene dose. Conclusion: Testing AChE-I serum concentration should be considered in patients without clinical response to treatment or those with severe side effects. Patients with donepezil drug levels outside the recommended range might additionally profit from CYP2D6 genotyping or treatment with an AChE-I independent of CYP metabolism.

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Clinical Response to Donepezil in Mild and Moderate Dementia: Relationship to Drug Plasma Concentration and CYP2D6 and APOE Genetic Polymorphisms

Cited by 20 publications

References 35 publications

<p>CYP2D6 Predicts Plasma Donepezil Concentrations in a Cohort of Thai Patients with Mild to Moderate Dementia</p>

<p>CYP2D6 Predicts Plasma Donepezil Concentrations in a Cohort of Thai Patients with Mild to Moderate Dementia</p>

Is it personalized treatment of dementia based on the CYP2D6 gene polymorphism possible?

<p>Therapeutic Drug Monitoring of Rivastigmine and Donepezil Under Consideration of CYP2D6 Genotype-Dependent Metabolism of Donepezil</p>

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