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Completed

NCT Number: NCT03349320

Response to Donepezil, Drug Plasma Concentration and the CYP2D6 and APOE Genetic Polymorphisms

Pharmacological treatment of AD is currently based on cholinesterase inhibitors (ChEI) and memantine, which have been shown to lead to modest, although effective, clinical benefits. Donepezil is a ChEI metabolized through the cytochrome P (CYP) 450, primarily by the 3A4 and 2D6 isoforms. The CYP2D6 gene presents polymorphisms that can alter its expression. The plasma therapeutic level ranges from 30 to 75 ng/mL, and 50% of acetylcholinesterase inhibition is achieved when the concentration reaches 15.6 ng/mL. An optimal plasma level is greater than 50 ng/mL.

These polymorphisms may influence the individual's response to treatment with donepezil and the concentration of the drug in AD patients, without achieving the desired effect. However, most of the individuals are EM, i.e., the metabolism of the drug occurs according to the expected kinetics and is associated with the presence of one or two wild-type alleles.

Objective: investigate the pattern of clinical response to donepezil in a group of patients with AD and AD with cerebrovascular disease (CVD) in relation to the plasmatic concentration of donepezil and polymorphisms of the CYP2D6 and apolipoprotein E (APOE) genes.

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Key information

Conditions

Late Onset Alzheimer Disease Alzheimer Disease Brain Diseases Central Nervous System Diseases Dementia Mental Disorders Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases Tauopathies

Sex eligibility

All sexes

Study type

Observational

About this study

Patients taking donepezil were seen four times (from June 2009 to March 2013) and were submitted to the MMSE test, the Consortium to Establish a Registry for Alzheimer'sDisease battery (CERAD), and the Pfeffer Functional Activities Questionnaire. CERAD memory evaluation was further divided into five components: incidental recall (CERAD151 INC), immediate recall 1 and 2 (CERAD-RM1, CERAD-RM2, respectively) and delayed recall after five minutes (CERAD-R). Each aspect was analyzed individually and compared between groups at baseline and after 12 months of treatment with donepezil. All patients had blood samples (10mL) collected to obtain donepezil plasmatic concentration (DPC) measurements and for APOE and CYP2D6 genotyping.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Patients fulfilling the National Institute on Aging and the Alzheimer's Association diagnostic criteria of probable AD dementia or the NINDS-AIREN (National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en Neurosciences) diagnostic criteria of AD with cerebrovascular disease (AD + CVD)
  • Patients presenting mild or moderate dementia according to the Clinical Dementia Rating (CDR), i.e., CDR 1 or 2, respectively

Exclusion criteria

  • Patients treated with ChEI or memantine before study entry
  • Patients diagnosed with frontotemporal dementia, dementia with Lewy bodies or vascular dementia,
  • Patients classified as CDR 3 or with Mild Cognitive Impairment
  • Illiterate patients
  • Disagreement between the first investigator and the treating physician regarding the diagnosis

Treatment and study plan

Primary outcomes

  1. Association among donepezil serum concentration after 3, 6, and 12 months of treatment onset and clinical response.

    Time frame: September, 2009 until March, 2013

    Evaluate the serum concentration of donepezil after 3, 6, and 12 months of treatment onset in patients considered good responders (i.e., those who had an increment >1 in MMSE in comparison to baseline assessment after 1 year of donepezil treatment) in contrast to those considered bad responders (i.e., who had a reduction, a stabilization or an increment of 1 in MMSE in comparison to baseline assessment after 1 year of donepezil treatment).

Secondary outcomes

  1. Evaluation of baseline cognitive performance

    Time frame: June, 2009 until March, 2012

    Assess the baseline cognitive performance among included patients (notedly, MMSE test, CERAD batteries, and in the Pfeffer Functional Activities Questionnaire).

  2. Evaluation of CYP2D6 and APOE polymorphisms

    Time frame: June, 2009 until March, 2012

    Evaluation of CYP2D6 and APOE polymorphisms among included patients.

  3. Evaluate donepezil serum concentration after 3 months of treatment onset.

    Time frame: September, 2009 until June, 2012

    Measurement of donepezil serum concentration after 3 months of treatment onset.

  4. Evaluate donepezil serum concentration after 6 months of treatment onset.

    Time frame: December, 2009 until September, 2012

    Measurement of donepezil serum concentration after 6 months of treatment onset.

  5. Evaluate donepezil serum concentration after 12 months of treatment onset.

    Time frame: June, 2010 until March, 2013

    Measurement of donepezil serum concentration after 12 months of treatment onset.

Sponsors and collaborators

Lead sponsor

Federal University of Minas Gerais

Other

Registry information

Official study title

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

Important dates

Study start
2009
Primary completion
2013
Study completion
2013
First posted
Nov 21, 2017
Registry last updated
Dec 18, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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