Pharmacogenetics of Donepezil and Memantine in Healthy Subjects

Ovejero‐Benito, María C.; Ochoa, Dolores; Enrique-Benedito, Teresa; Peso-Casado, Miriam del; Zubiaur, Pablo; Navares, Marcos; Román, Manuel; Abad‐Santos, Francisco

doi:10.3390/jpm12050788

Cited by 5 publications

(7 citation statements)

References 60 publications

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“…Pleurothotonus, myoclonus, and dystonia may be due to the overactivation of nicotinic receptors or a dopaminergic-cholinergic imbalance, which have also been reported in related studies ( Zannas et al, 2014 ). Finally, although somnolence and lethargy are relatively less harmful and ultimately difficult to detect in the clinical setting, our results, together with those of other studies, suggest that they are among the adverse effects of donepezil administration in combination with memantine ( Ovejero-Benito et al, 2022 ; Kose et al, 2023 ). Although adverse effects such as headache ( Majidazar et al, 2022 ; Ovejero-Benito et al, 2022 ; Kose et al, 2023 ), low hemoglobin ( Grossberg et al, 2013 ), rhabdomyolysis ( Fleet et al, 2019 ), nasopharyngitis ( Atri et al, 2013 ; Wong, 2016 ), and weakness ( Babai et al, 2010 ) were not found in our study, they have been reported in other studies.…”

Section: Discussionsupporting

confidence: 55%

Adverse event profile of memantine and donepezil combination therapy: a real-world pharmacovigilance analysis based on FDA adverse event reporting system (FAERS) data from 2004 to 2023

Yang,

Wei,

Tian

et al. 2024

Front. Pharmacol.

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BackgroundDonepezil in combination with memantine is a widely used clinical therapy for moderate to severe dementia. However, real-world population data on the long-term safety of donepezil in combination with memantine are incomplete and variable. Therefore, the aim of this study was to analyze the adverse events (AEs) of donepezil in combination with memantine according to US Food and Drug Administration Adverse Event Reporting System (FAERS) data to provide evidence for the safety monitoring of this therapy.MethodsWe retrospectively analyzed reports of AEs associated with the combination of donepezil and memantine from 2004 to 2023 extracted from the FAERS database. Whether there was a significant association between donepezil and memantine combination therapy and AEs was assessed using four disproportionality analysis methods, namely, the reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker methods. To further investigate potential safety issues, we also analyzed differences and similarities in the time of onset and incidence of AEs stratified by sex and differences and similarities in the incidence of AEs stratified by age.ResultsOf the 2,400 adverse drug reaction (ADR) reports in which the combination of donepezil and memantine was the primary suspected drug, most of the affected patients were female (54.96%) and older than 65 years of age (79.08%). We identified 22 different system organ classes covering 100 AEs, including some common AEs such as dizziness and electrocardiogram PR prolongation; fall, pleurothotonus and myoclonus were AEs that were not listed on the drug label. Moreover, we obtained 88 reports of AEs in men and 100 reports of AEs in women; somnolence was a common AE in both men and women and was more common in women, whereas pleurothotonus was a more common AE in men. In addition, we analyzed 12 AEs in patients younger than 18 years, 16 in patients between 18 and 65 years, and 113 in patients older than 65 years. The three age groups had distinctive AEs, but lethargy was the common AE among all age groups. Finally, the median time to AE onset was 19 days in all cases. In both men and women, most AEs occurred within a month of starting donepezil plus memantine, but some continued after a year of treatment.ConclusionOur study identified potential and new AEs of donepezil in combination with memantine; some of these AEs were the same as in the specification, and some of the AE signals were not shown in the specification. In addition, there were sex and age differences in some of the AEs. Therefore, our findings may provide valuable insights for further studies on the safety of donepezil and memantine combination therapy, which are expected to contribute to the safe use of this therapy in clinical practice.

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Section: Discussionsupporting

confidence: 55%

Adverse event profile of memantine and donepezil combination therapy: a real-world pharmacovigilance analysis based on FDA adverse event reporting system (FAERS) data from 2004 to 2023

Yang,

Wei,

Tian

et al. 2024

Front. Pharmacol.

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“…Ovejero-Benito and colleagues investigated the association of 67 polymorphisms in 21 genes, including CYP2D6, CYP2C9, CYP2A6, ABCB1, and genes coding for different neurotransmitter receptors, with donepezil or memantine pharmacokinetics and safety. The authors reported no significant association of analyzed SNPs with both memantine and donepezil pharmacokinetics or adverse drug reactions [196].…”

Section: Pharmacogenomics Of Cognitive Symptoms: Conventional Anti-de...mentioning

confidence: 94%

“…Donepezil is the most prescribed drug for the treatment of cognitive symptoms in dementia [195]. Different CYP2D6 variants have been studied in order to assess their influence on donepezil efficacy and safety in AD patients [195][196][197][198][199][200][201][202][203][204]. These variants include rs1065852, rs1080985, CYP2D6*3 (rs35742686, 2549delA), CYP2D6*4 (rs3892097, 1846G>A), CYP2D6*6 (rs5030655, 1707delT), CYP3A4*1B (rs2740574, −392A>G), and CYP2D6*10 (rs1065852, 100C>T); however, the results are inconsistent [203].…”

Section: Pharmacogenomics Of Cognitive Symptoms: Conventional Anti-de...mentioning

confidence: 99%

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Pharmacogenomics of Dementia: Personalizing the Treatment of Cognitive and Neuropsychiatric Symptoms

Vuic,

Milos,

Tudor

et al. 2023

Genes

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Dementia is a syndrome of global and progressive deterioration of cognitive skills, especially memory, learning, abstract thinking, and orientation, usually affecting the elderly. The most common forms are Alzheimer’s disease, vascular dementia, and other (frontotemporal, Lewy body disease) dementias. The etiology of these multifactorial disorders involves complex interactions of various environmental and (epi)genetic factors and requires multiple forms of pharmacological intervention, including anti-dementia drugs for cognitive impairment, antidepressants, antipsychotics, anxiolytics and sedatives for behavioral and psychological symptoms of dementia, and other drugs for comorbid disorders. The pharmacotherapy of dementia patients has been characterized by a significant interindividual variability in drug response and the development of adverse drug effects. The therapeutic response to currently available drugs is partially effective in only some individuals, with side effects, drug interactions, intolerance, and non-compliance occurring in the majority of dementia patients. Therefore, understanding the genetic basis of a patient’s response to pharmacotherapy might help clinicians select the most effective treatment for dementia while minimizing the likelihood of adverse reactions and drug interactions. Recent advances in pharmacogenomics may contribute to the individualization and optimization of dementia pharmacotherapy by increasing its efficacy and safety via a prediction of clinical outcomes. Thus, it can significantly improve the quality of life in dementia patients.

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“…The development of new drug molecules is a demanding process in terms of time and resources [ 1 ]. In Alzheimer’s disease (AD), the translational gap between basic research and clinical trials considerably influences the release rate of new drugs [ 2 ], while the available oral treatments are therapeutically insufficient due to several reasons, such as the extended hepatic metabolism and limited brain targeting that can result in interindividual variability of drug responses [ 3 , 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Donepezil Brain and Blood Pharmacokinetic Modeling after Nasal Film and Oral Solution Administration in Mice

et al. 2023

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Intranasal delivery is a non-invasive mode of administration, gaining popularity due to its potential for targeted delivery to the brain. The anatomic connection of the nasal cavity with the central nervous system (CNS) is based on two nerves: olfactory and trigeminal. Moreover, the high vasculature of the respiratory area enables systemic absorption avoiding possible hepatic metabolism. Due to these physiological peculiarities of the nasal cavity, compartmental modeling for nasal formulation is considered a demanding process. For this purpose, intravenous models have been proposed, based on the fast absorption from the olfactory nerve. However, most of the sophisticated approaches are required to describe the different absorption events occurring in the nasal cavity. Donepezil was recently formulated in the form of nasal film ensuring drug delivery in both bloodstream and the brain. In this work, a three-compartment model was first developed to describe donepezil oral brain and blood pharmacokinetics. Subsequently, using parameters estimated by this model, an intranasal model was developed dividing the administered dose into three fractions, corresponding to absorption directly to the bloodstream and brain, as well as indirectly to the brain expressed through transit compartments. Hence, the models of this study aim to describe the drug flow on both occasions and quantify the direct nose-to-brain and systemic distribution.

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Pharmacogenetics of Donepezil and Memantine in Healthy Subjects

Cited by 5 publications

References 60 publications

Adverse event profile of memantine and donepezil combination therapy: a real-world pharmacovigilance analysis based on FDA adverse event reporting system (FAERS) data from 2004 to 2023

Adverse event profile of memantine and donepezil combination therapy: a real-world pharmacovigilance analysis based on FDA adverse event reporting system (FAERS) data from 2004 to 2023

Pharmacogenomics of Dementia: Personalizing the Treatment of Cognitive and Neuropsychiatric Symptoms

Donepezil Brain and Blood Pharmacokinetic Modeling after Nasal Film and Oral Solution Administration in Mice

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