Guiding safer risperidone prescribing in Alzheimer's disease with therapeutic drug monitoring.

Previous analysis of pharmacokinetic data on risperidone-treated patients with dementia predicted that 20% had concentration-to-dose (C/D) ratios of the active moiety (risperidone and 9-hydroxy(OH)-risperidone) above 14 ng/mL per mg/day, which were in turn associated with a greater risk of extrapyramidal side effects. This study aimed to further explore risperidone pharmacokinetics in a second dataset. Nonlinear mixed effects modelling, using a Bayesian approach, was applied to data from a randomized controlled trial of risperidone in people with dementia. Covariates included age and glomerular filtration rate (GFR). Age had a significant effect on risperidone clearance (β = -1.5) and GFR on 9-OH-risperidone clearance (β = 0.2). The model predicted that 26.2% (95% confidence interval 18.6-32.6%) had C/D ratios above 14 ng/mL per mg/day. These findings confirm the importance of age-related risperidone dose adjustments and argue strongly for therapeutic drug monitoring in the initial stages of treatment to identify those at greatest risk of toxicity.