title: Dopamine D2/3 Receptor Occupancy Following Dose Reduction Is Predictable With Minimal Plasma Antipsychotic Concentrations: An Open-Label Clinical Trial.
abstract: BACKGROUND
  Population pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D2/3 receptors (D2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested.
  
  
  METHODS
  Two blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1 ± 7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [(11)C]-raclopride positron emission tomography scan to measure D2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value.
  
  
  RESULTS
  The mean (95% CI) prediction errors for the prediction of D2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D2/3R occupancy levels were highly correlated (r = 0.67, P = .001 for olanzapine; r = 0.67, P = .02 for risperidone).
  
  
  CONCLUSIONS
  D2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D2/3R occupancy on an individual basis.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, Canada; Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; hiroyuki.uchida.hu@gmail.com.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uchida
authors.affiliation: Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, Canada; Indiana University School of Medicine, Division of Clinical Pharmacology, Indianapolis, IN;
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
authors.affiliation: Multimodal Imaging Group - Research Imaging Centre and Department of Psychiatry, University of Toronto, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada;
authors.forename: Fernando
authors.initials: F
authors.lastname: Caravaggio
authors.affiliation: Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan;
authors.forename: Takefumi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Multimodal Imaging Group - Research Imaging Centre and Department of Psychiatry, University of Toronto, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada;
authors.forename: Eric
authors.initials: E
authors.lastname: Plitman
authors.affiliation: Multimodal Imaging Group - Research Imaging Centre and.
authors.forename: Wanna
authors.initials: W
authors.lastname: Mar
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, Canada;
authors.forename: Philip
authors.initials: P
authors.lastname: Gerretsen
authors.affiliation: Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada; Campbell Research Institute, Centre for Addiction and Mental Health, Toronto, Canada;
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Pollock
authors.affiliation: Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada; Campbell Research Institute, Centre for Addiction and Mental Health, Toronto, Canada;
authors.forename: Benoit H
authors.initials: BH
authors.lastname: Mulsant
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, Canada;
authors.forename: David C
authors.initials: DC
authors.lastname: Mamo
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, Canada;
authors.forename: Ariel
authors.initials: A
authors.lastname: Graff-Guerrero
mesh_terms: D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000378:metabolism; D001569:Benzodiazepines / Q000008:administration & dosage / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002250:Carbon Radioisotopes; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D000068882:Paliperidone Palmitate / Q000378:metabolism; D049268:Positron-Emission Tomography; D011446:Prospective Studies; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D018967:Risperidone / Q000008:administration & dosage / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D001569:Benzodiazepines; D020891:Raclopride; D018967:Risperidone; D000077152:Olanzapine; D000068882:Paliperidone Palmitate
keywords: PET; antipsychotics; dopamine; olanzapine; population pharmacokinetics; prediction; risperidone; schizophrenia