title: Predicting plasma concentration of risperidone associated with dosage change:  a population pharmacokinetic study.
abstract: BACKGROUND
  Due to high interindividual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics relies on clinical trial and error. This blind process of upward or downward clinical dose titration carries a risk of relapse and adverse effects in the treatment of schizophrenia. Using population pharmacokinetic methods, the authors therefore sought to predict plasma concentrations of risperidone (RIS) plus 9-hydroxyrisperidone (9-OH-RIS) before a dosage change.
  
  
  METHODS
  Two plasma samples were collected at 2 separate given time points for the measurement of RIS and 9-OH-RIS concentrations from 50 patients with schizophrenia or schizoaffective disorder maintained on risperidone (mean ± SD age = 56 ± 15 years; 39 men). After an oral risperidone dose adjustment, a third sample was collected. The plasma concentration of the third sample was individually predicted in a blinded fashion with the 2 baseline plasma concentrations before dose adjustment and clinical and demographic information, using the mixed-effects model with NONMEM that was derived from the data of the Clinical Antipsychotic Trials in Intervention Effectiveness study.
  
  
  RESULTS
  The mean (95% confidence interval) prediction errors (in ng/mL) were as low as 0.0 (-1.3 to 1.4) for RIS and 1.0 (-1.1 to 3.0) for 9-OH-RIS. The observed and predicted concentrations of RIS and 9-OH-RIS were highly correlated (r = 0.96, P < 0.0001 and r = 0.92, P < 0.0001, respectively).
  
  
  CONCLUSIONS
  Antipsychotic plasma concentrations can be predicted before risperidone dose adjustment. In light of the known relationship between plasma drug concentration, dopamine D2 receptor occupancy, and clinical effects, our results confirm that individualized dosing with the measurement of antipsychotic plasma concentrations has the potential for bedside clinical application.
authors.affiliation: Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan. mcn41320@biglobe.ne.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uchida
authors.forename: David C
authors.initials: DC
authors.lastname: Mamo
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Pollock
authors.forename: Takefumi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kenichi
authors.initials: K
authors.lastname: Tsunoda
authors.forename: Koichiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Masaru
authors.initials: M
authors.lastname: Mimura
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D000068882:Paliperidone Palmitate; D011618:Psychotic Disorders / Q000188:drug therapy; D011743:Pyrimidines / Q000493:pharmacokinetics*; D018967:Risperidone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012559:Schizophrenia / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D018967:Risperidone; D000068882:Paliperidone Palmitate