Population pharmacokinetic modeling of risperidone and 9-hydroxyrisperidone to estimate CYP2D6 subpopulations in children and adolescents.
Population pharmacokinetic modeling of risperidone and 9-hydroxyrisperidone to estimate CYP2D6 subpopulations in children and adolescents.
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DOI：
10.1097/ftd.0b013e318261c240
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发表时间：
2012-10
影响因子：
2.5
通讯作者：
Vinks AA
中科院分区：
文献类型：
--
作者：
Sherwin CM;Saldaña SN;Bies RR;Aman MG;Vinks AA
The study aims were to characterize risperidone and (±)-9-hydroxyrisperidone pharmacokinetic variability in children and adolescents and to evaluate covariate effects on pharmacokinetic parameters. 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. 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. 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.
