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

Late Onset Alzheimer Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03349320
• Other study ID #: 0172 /2010
• Status: Completed
• Phase: N/A
• First received: June 21, 2017
• Last updated: December 14, 2017
• Start date: June 2009
• Est. completion date: March 2013

Study information

• Verified date: December 2017
• Source: Federal University of Minas Gerais
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. completion date: March 2013
• Est. primary completion date: March 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Alzheimer Disease
• Late Onset Alzheimer Disease

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Federal University of Minas Gerais

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Evaluation of baseline cognitive performance	Assess the baseline cognitive performance among included patients (notedly, MMSE test, CERAD batteries, and in the Pfeffer Functional Activities Questionnaire).	June, 2009 until March, 2012
Secondary	Evaluation of CYP2D6 and APOE polymorphisms	Evaluation of CYP2D6 and APOE polymorphisms among included patients.	June, 2009 until March, 2012
Secondary	Evaluate donepezil serum concentration after 3 months of treatment onset.	Measurement of donepezil serum concentration after 3 months of treatment onset.	September, 2009 until June, 2012
Secondary	Evaluate donepezil serum concentration after 6 months of treatment onset.	Measurement of donepezil serum concentration after 6 months of treatment onset.	December, 2009 until September, 2012
Secondary	Evaluate donepezil serum concentration after 12 months of treatment onset.	Measurement of donepezil serum concentration after 12 months of treatment onset.	June, 2010 until March, 2013