title: Population pharmacokinetic modeling of risperidone and 9-hydroxyrisperidone to estimate CYP2D6 subpopulations in children and adolescents.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 6018, Cincinnati, OH 45229-3039, USA.
authors.forename: Catherine M T
authors.initials: CM
authors.lastname: Sherwin
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Saldaña
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
authors.forename: Michael G
authors.initials: MG
authors.lastname: Aman
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
mesh_terms: D000293:Adolescent; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D007555:Isoxazoles / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D001523:Mental Disorders / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D000068882:Paliperidone Palmitate; D010641:Phenotype; D011446:Prospective Studies; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D018967:Risperidone / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D000068882:Paliperidone Palmitate