Reeves, S;
Howard, R;
Bramon, E;
Liu, K;
Bertrand, J;
Uchida, H;
yoshida, K;
... ozer, M; + view all
(2021)
Towards safer risperidone prescribing in Alzheimer's disease.
British Journal of Psychiatry
, 218
(5)
pp. 268-275.
10.1192/bjp.2020.225.
Preview |
Text (Accepted Manuscript Request)
Reeves_Towards Safer Risperidone Prescribing in Alzheimer's disease_AAM2.pdf - Accepted Version Download (897kB) | Preview |
Preview |
Image (Supplementary Material)
Fig 1. Active Moiety Concentration to Dose Ratio_240220.tif - Accepted Version Download (1MB) | Preview |
Preview |
Image (Supplementary Material)
Fig 2. Simulated trough 9-OH-risperidone and EPS.tif - Accepted Version Download (4MB) | Preview |
Preview |
Image (Supplementary Material)
Supplementary Fig.1 VPC Risp PM NM 9OHrisp_.tif - Accepted Version Download (7MB) | Preview |
Abstract
Background: In the treatment of psychosis, agitation and aggression in Alzheimer's disease, guidelines emphasise the need to ‘use the lowest possible dose’ of antipsychotic drugs, but provide no information on optimal dosing. / Aims: This analysis investigated the pharmacokinetic profiles of risperidone and 9-hydroxy (OH)-risperidone, and how these related to treatment-emergent extrapyramidal side-effects (EPS), using data from The Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease study (Clinicaltrials.gov identifier: NCT00015548). / Method: A statistical model, which described the concentration–time course of risperidone and 9-OH-risperidone, was used to predict peak, trough and average concentrations of risperidone, 9-OH-risperidone and ‘active moiety’ (combined concentrations) (n = 108 participants). Logistic regression was used to investigate the associations of pharmacokinetic biomarkers with EPS. Model-based predictions were used to simulate the dose adjustments needed to avoid EPS. / Results: The model showed an age-related reduction in risperidone clearance (P < 0.0001), reduced renal elimination of 9-OH-risperidone (elimination half-life 27 h), and slower active moiety clearance in 22% of patients, (concentration-to-dose ratio: 20.2 (s.d. = 7.2) v. 7.6 (s.d. = 4.9) ng/mL per mg/day, Mann–Whitney U-test, P < 0.0001). Higher trough 9-OH-risperidone and active moiety concentrations (P < 0.0001) and lower Mini-Mental State Examination (MMSE) scores (P < 0.0001), were associated with EPS. Model-based predictions suggest the optimum dose ranged from 0.25 mg/day (85 years, MMSE of 5), to 1 mg/day (75 years, MMSE of 15), with alternate day dosing required for those with slower drug clearance. / Conclusions: Our findings argue for age- and MMSE-related dose adjustments and suggest that a single measure of the concentration-to-dose ratio could be used to identify those with slower drug clearance.
Archive Staff Only
 |
View Item |
