The primary goal of this revised application (MH64173), which is ancillary to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), is to reliably capture the concentration exposure of the antipsychotics (risperidone, olanzapine, ziprasidone, fluphenazine, perphenazine, and clozapine) using mixed effect population pharmacokinetic methodologies. The population pharmacokinetic approach is ideally suited for analyzing drug concentration data from large clinical intervention trials because patient-specific as well as overall population pharmacokinetic parameters can be determined using only a few plasma samples per patient. An understanding of pharmacokinetic variability is essential to rational drug prescribing. The population pharmacokinetic approach will permit determination of the extent of variability in drug exposure associated with the use of atypical antipsychotics in large populations under conditions that mirror clinical practice. In addition, the ability of population pharmacokinetic models to capture subjects' drug exposure utilizing single concentration measurements will be assessed in this study. Population pharmacokinetics has also been successfully used to identify sources of variability in drug concentration exposure. Therefore, this ancillary study will provide an innovative way to make optimal use of plasma samples that are being obtained in the CATIE trials. The CATIE trials will recruit up to 2,250 patients providing from 1 to 6 plasma concentration samples per subject for each medication. A separate population pharmacokinetic model will be constructed for each drug incorporating covariate effects. Specific covariates will be then be evaluated as potential contributors to drug exposure variability. Demographic covariates to be examined are age, sex, race/minority status, and body mass index. The potential impact of additional covariates such as prior medication exposure, concomitant medications, smoking status, estimated renal clearance, and treatment adherence will also be assessed. By providing pharmacokinetic data on the atypical antipsychotics under """"""""real world"""""""" conditions, this study has broad public health implications, leading to greater awareness of the need to individualize antipsychotics pharmacotherapy for patients suffering from either schizophrenia or Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH064173-04
Application #
6794024
Study Section
Special Emphasis Panel (ZMH1-CRB-B (03))
Program Officer
Evans, Jovier D
Project Start
2001-09-01
Project End
2007-08-31
Budget Start
2004-09-01
Budget End
2007-08-31
Support Year
4
Fiscal Year
2004
Total Cost
$260,035
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Takeuchi, Hiroyoshi; Fervaha, Gagan; Uchida, Hiroyuki et al. (2014) Impact of once- versus twice-daily perphenazine dosing on clinical outcomes: an analysis of the CATIE data. J Clin Psychiatry 75:506-11
Yoshida, Kazunari; Bies, Robert R; Suzuki, Takefumi et al. (2014) Tardive dyskinesia in relation to estimated dopamine D2 receptor occupancy in patients with schizophrenia: analysis of the CATIE data. Schizophr Res 153:184-8
Tsuboi, Takashi; Bies, Robert R; Suzuki, Takefumi et al. (2013) Hyperprolactinemia and estimated dopamine D2 receptor occupancy in patients with schizophrenia: analysis of the CATIE data. Prog Neuropsychopharmacol Biol Psychiatry 45:178-82
Sakurai, Hitoshi; Bies, Robert R; Stroup, Scott T et al. (2013) Dopamine D2 receptor occupancy and cognition in schizophrenia: analysis of the CATIE data. Schizophr Bull 39:564-74
Moriguchi, Sho; Bies, Robert R; Remington, Gary et al. (2013) Estimated dopamine D? receptor occupancy and remission in schizophrenia: analysis of the CATIE data. J Clin Psychopharmacol 33:682-5
Takeuchi, Hiroyoshi; Suzuki, Takefumi; Bies, Robert R et al. (2013) Estimated dopamine D2 receptor occupancy from plasma concentrations of atypical antipsychotics and subjective experience/drug attitude in schizophrenia: an analysis of the CATIE data. Schizophr Res 150:373-9
Sherer, Eric A; Sale, Mark E; Pollock, Bruce G et al. (2012) Application of a single-objective, hybrid genetic algorithm approach to pharmacokinetic model building. J Pharmacokinet Pharmacodyn 39:393-414
Wessels, Alette M; Bies, Robert R; Pollock, Bruce G et al. (2011) Population pharmacokinetic modeling of ziprasidone in patients with schizophrenia from the CATIE study. J Clin Pharmacol 51:1587-91
Wessels, Alette M; Pollock, Bruce G; Anyama, Norbert G et al. (2010) Association of 9-hydroxy risperidone concentrations with risk of switching or discontinuation in the clinical antipsychotic trial of intervention effectiveness-Alzheimer's disease trial. J Clin Psychopharmacol 30:683-7
Jin, Yuyan; Pollock, Bruce G; Coley, Kim et al. (2010) Population pharmacokinetics of perphenazine in schizophrenia patients from CATIE: impact of race and smoking. J Clin Pharmacol 50:73-80

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