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

NCT03349320 | Completed

• 1 other identifier: 0172 /2010
• Study Type: observational
• Target: 37
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Late Onset Alzheimer Disease

Keywords

Alzheimer; APOE; CYP2D6; Donepezil; Genetics

Outcome Measures

Primary Outcomes (1)

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

  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).

  September, 2009 until March, 2013

Secondary Outcomes (5)

• Evaluation of baseline cognitive performance

  June, 2009 until March, 2012

• Evaluation of CYP2D6 and APOE polymorphisms

  June, 2009 until March, 2012

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

  September, 2009 until June, 2012

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

  December, 2009 until September, 2012

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

  June, 2010 until March, 2013

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

A longitudinal, naturalist study, conducted at the Geriatric Outpatient Clinic of the Hospital das Clínicas at the Federal University of Minas Gerais (UFMG), in Belo Horizonte (MG), Brazil. The sample comprised patients evaluated from June, 2009 until March, 2013

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Federal University of Minas Gerais: lead

Biospecimen

Retention: SAMPLES WITH DNA

A blood sample was drawn from the patients on the first consultation for use in DNA extraction and Apolipoprotein E (APOE) genotyping. For the patients who were taking donepezil, after three, six and twelve months of treatment another blood sample were also drawn, separated in plasma and kept into the freezer at - 70 Celsius degree for further analysis of serum level of donepezil.

MeSH Terms

Conditions

Alzheimer Disease

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Study Officials

• Paulo Caramelli, MD, PhD

  Federal University of Minas Gerais

  STUDY CHAIR

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Physician, Geriatrician, MD, PhD

Study Record Dates

• First Submitted: June 21, 2017
• First Posted: November 21, 2017
• Study Start: June 1, 2009
• Primary Completion: March 1, 2013
• Study Completion: March 1, 2013
• Last Updated: December 18, 2017

Record last verified: 2017-12