Risperidone plasma concentrations are associated with side-effects and effectiveness in children and adolescents with autism spectrum disorder.

AIM Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but is associated with serious side-effects, including weight gain. This study assessed the relationship of risperidone and 9-hydroxyrisperidone trough concentrations, maximum concentrations and 24-h area-under-the curves with BMI z-scores in children and adolescents with autism spectrum disorder (ASD) and behavioral problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side-effects and effectiveness. METHODS Forty-two children and adolescents (32 males) aged 6-18 years were included in a 24 week prospective observational trial. Drug plasma concentrations, side-effects and effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were measured. Non-linear mixed-effects modeling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9-hydroxyrisperidone concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-h area-under-the curves were analyzed to predict outcomes using generalized and linear mixed-effects models. RESULTS A risperidone two-compartment model combined with a 9-hydroxyrisperidone one-compartment model best described the measured concentrations. Off all pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z-scores during follow-up (p<0.001). Higher sum trough concentrations also predicted more sedation (p<0.05), higher prolactin levels (<0.001), and more effectiveness measured with ABC-irritability score (p<0.01). CONCLUSION Our results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioral problems.