Population pharmacokinetic modeling of risperidone and 9-hydroxyrisperidone to estimate CYP2D6 subpopulations in children and adolescents

Catherine M T Sherwin, Shannon N. Saldaña, Robert Bies, Michael G. Aman, Alexander A. Vinks

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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 (±)-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.

Original languageEnglish
Pages (from-to)535-544
Number of pages10
JournalTherapeutic Drug Monitoring
Volume34
Issue number5
DOIs
StatePublished - Oct 2012

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Cytochrome P-450 CYP2D6
Risperidone
Pharmacokinetics
Population
Weights and Measures
Paliperidone Palmitate
Genotype
Phenotype

Keywords

  • adolescent
  • children
  • CYP2D6
  • NONMEM
  • pharmacokinetics
  • risperidone

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Population pharmacokinetic modeling of risperidone and 9-hydroxyrisperidone to estimate CYP2D6 subpopulations in children and adolescents. / Sherwin, Catherine M T; Saldaña, Shannon N.; Bies, Robert; Aman, Michael G.; Vinks, Alexander A.

In: Therapeutic Drug Monitoring, Vol. 34, No. 5, 10.2012, p. 535-544.

Research output: Contribution to journalArticle

Sherwin, Catherine M T ; Saldaña, Shannon N. ; Bies, Robert ; Aman, Michael G. ; Vinks, Alexander A. / Population pharmacokinetic modeling of risperidone and 9-hydroxyrisperidone to estimate CYP2D6 subpopulations in children and adolescents. In: Therapeutic Drug Monitoring. 2012 ; Vol. 34, No. 5. pp. 535-544.
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