Population Pharmacokinetic Modeling of Risperidone and 9-Hydroxyrisperidone to Estimate CYP2D6 Subpopulations in Children and Adolescents
Document Type
Article
Publication Date
10-2012
Abstract
AIM
The study aims were to characterize risperidone and (±)-9-hydroxyrisperidone pharmacokinetic variability in children and adolescents and to evaluate covariate effects on pharmacokinetic parameters.
METHODS
Steady-state samples were drawn at pre-dose, 1, 2, 4, and 7 hours post-dose; CYP2D6 genotypes were available for 28 subjects. A non-linear mixed-effects model (NONMEM®) modeled the pharmacokinetics of risperidone and (±)-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 one-compartment mixture model described risperidone and (±)-9-hydroxyrisperidone clearances for three CYP2D6 metabolizer subpopulations: extensive (EM), intermediate (IM), and poor (PM). Weight significantly affected (±)-9-hydroxyrisperidone clearance. Clearance estimates in the mixture model were PM 9.38 L/h, IM 29.2 L/h, and EM 37.4 L/h.
CONCLUSION
Active moiety [risperidone plus (±)-9-hydroxyrisperidone] pharmacokinetic variability and the covariate effects were better explained with addition of metabolite pharmacokinetic parameters. This model may aid development of individualized risperidone dosing regimens in children and adolescents.
Repository Citation
Sherwin, C. M.,
Saldaña, S. N.,
Bies, R. R.,
Aman, M. G.,
& Vinks, A. A.
(2012). Population Pharmacokinetic Modeling of Risperidone and 9-Hydroxyrisperidone to Estimate CYP2D6 Subpopulations in Children and Adolescents. Therapeutic Drug Monitoring, 34 (5), 535-544.
https://corescholar.libraries.wright.edu/pediatrics/288
DOI
10.1097/FTD.0b013e318261c240
