Population pharmacokinetics of oral risperidone in children, adolescents and adults with psychiatric disorders

Background and Objectives: Oral risperidone is licensed globally for the treatment of several psychiatric disorders in children, adolescents and adults. The pharmacokinetic profile of risperidone is well documented in adults. In this study, the pharmacokinetics of oral risperidone in children and adolescents were investigated along with population pharmacokinetics in paediatric and adult subjects. Methods: The pharmacokinetics of oral risperidone in children and adolescents were investigated through non-compartmental analysis (paediatric phase I study; n = 24) and population pharmacokinetic analysis using nonlinear mixed-effects modelling software (NONMEM (R)) on a pooled database including both paediatric (n = 304) and adult (n = 476) data. Monte Carlo simulations were performed to evaluate the relevance of the effects of covariates on the plasma exposure of the active antipsychotic fraction. Results: Non-compartmental pharmacokinetic analysis showed that, after correcting doses for bodyweight, plasma exposure was comparable between children and adolescents and in line with historical adult data. Pooled population pharmacokinetic analysis, using a priori allometric scaling of the clearance and volume of distribution, showed that apparent renal clearance of the active antipsychotic fraction was 0.96 L/h and apparent metabolic clearance was 4.26 L/h for a typical patient weighing 62 kg, aged 18.1 years, with a median creatinine clearance of 117.6 mL/min. For a typical child (11 years, 39 kg), adolescent (15 years, 60 kg) and adult (33 years, 70 kg), the apparent total oral clearance values were 4.35, 5.30 and 5.04 L/h, respectively. None of the tested demographic or biochemical characteristics were found to have a relevant effect on any of the pharmacokinetic parameters of risperidone and the active antipsychotic fraction. Conclusion: Population pharmacokinetics and Monte Carlo simulations demonstrated similar pharmacokinetics of risperidone in children, adolescents and adults