Fatores preditivos de resposta aos inibidores da colinesterase, dosagem da concentração plasmática de donepezila e avaliação farmacogenética em pacientes com doença de Alzheimer e demência mista: estudo naturalístico

Abstract

Background: Naturalistic studies on Alzheimers disease, which evaluate individuals in their usual life style, without selecting them previously, showing their comorbidities and different ages, are rare in Brazil. Objective: This study aimed to investigate the demographic, clinical and genetic factors that might be predictive of good response to cholinesterase inhibitors (ChEI) treatment in Alzheimers disease (AD) and AD + cerebrovascular disease (CVD); to measure the plasmatic concentration of donepezil in patients under treatment; to verify the correlation between the concentration of donepezil with the polymorphisms of Apoliprotein E (APOE) and of CYP2D6 genes, as well as with the clinical response. Patients and Methods: A total of 129 patients diagnosed with AD or AD + CVD, with mild-to-moderate dementia participated of this study, but only 97 patients completed the study after a 12-month of treatment. They were evaluated at baseline and three, six and 12 months of ChEI (donepezil, galantamine or rivastigmine) treatment. APOE genotyping were determined for all participants and CYP2D6 polymorphisms for those taking donepezil. At each visit, were administrated cognitive, functional, mood and behavior scales, as well as measured plasma concentration of donepezil in the last three visits. Patients were classified according to the score on the Mini-Mental State of Examination (MMSE). Good responders were defined as those scoring 2 in the MMSE at 12 months comparing with the MMSE at baseline. Results: The rate of good clinical response was 27.8%. Half of them carried the allele APOE4. In a longitudinal analysis, patients with mild AD and also patients who scored 2 in the MMSE at three months had more chance to be good responders at 12 months. Clinical response to donepezil was investigated in relation to the drug plasma concentration and the presence of the APOE and CYP2D6 polymorphisms in 42 patients taking the medication (10 mg) for 12 months. There was no correlation between APOE and CYP2D6 polymorphisms with the pattern of clinical response. However, good and neutral responders had higher plasmatic concentration of donepezil at 12 months of treatment when compared to three and six months, suggesting the occurrence of better response with higher plasmatic concentration of the drug. Conclusion: The main predictive factors of good response to these drugs at 12 months of treatment were mild dementia and the presence of good response at three months of medication use. There was no correlation between the polymorphisms of APOE, CYP2D6 and the pattern of clinical response. The plasmatic concentration of donepezil was higher in good and neutral responders.