Population Pharmacokinetic Modeling of Risperidone and 9-Hydroxyrisperidone to Estimate CYP2D6 Subpopulations in Children and Adolescents

Aim: The study aims were to characterize risperidone and (+/-)-9-hydroxyrisperidone pharmacokinetic (PK) variability in children and adolescents and to evaluate covariate effects on PK parameters. Methods: Steady-state samples were drawn at predose, 1, 2, 4, and 7 hours postdose; cytochrome P450 2D6 (CYP2D6) genotypes were available for 28 subjects. A nonlinear mixed-effects model (NONMEM) modeled the PKs of risperidone and (perpendicular to)-9-hydroxyrisperidone; covariates included age, weight, sex, and CYP2D6 phenotype. The model included 497 observations [risperidone (n = 163), (+) and (-)-9-hydroxyrisperidone (n = 334)] from 45 subjects aged 3-18.3 (mean 9.6 +/- 3.7) years, weighing 16.8-110 (43 +/- 20.2) kg. Results: A 1-compartment mixture model described risperidone and (+)-9-hydroxyrisperidone clearances for 3 CYP2D6 metabolizer subpopulations: extensive, intermediate, and poor. Weight significantly affected (+/-)- 9-hydroxyrisperidone clearance. Clearance estimates in the mixture model were poor metabolizer 9.38 L/h, intermediate metabolizer 29.2 L/h, and extensive metabolizer 37.4 L/h. Conclusion: Active moiety [risperidone plus (+/-)-9-hydroxyrisperidone] PK variability and the covariate effects were better explained with the addition of metabolite PK parameters. This model may aid the development of individualized risperidone dosing regimens in children and adolescents.