Document Detail


Predicting brain occupancy from plasma levels using PET: superiority of combining pharmacokinetics with pharmacodynamics while modeling the relationship.
MedLine Citation:
PMID:  22186667     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Positron emission tomography (PET) studies of dopamine receptor occupancy can be used to assess dosing of antipsychotics. Typically, studies of antipsychotics have applied pharmacodynamic (PD) modeling alone to characterize the relationship between antipsychotic dose and its effect on the brain. However, a limitation of this approach is that it does not account for the discrepancy between the time courses of plasma concentration and receptor occupancy by antipsychotics. Combined pharmacokinetic-PD (PK-PD) modeling, by incorporating the time dependence of occupancy, is better suited for the reliable analysis of the concentration-occupancy relationship. To determine the effect of time on the concentration-occupancy relationship as a function of analysis approach, we measured dopamine receptor occupancy after the administration of aripiprazole using [(11)C]raclopride PET and obtained serial measurements of the plasma aripiprazole concentration in 18 volunteers. We then developed a PK-PD model for the relationship, and compared it with conventional approach (PD modeling alone). The hysteresis characteristics were observed in the competitor concentration-occupancy relationship and the value of EC(50) was different according to the analysis approach (EC(50) derived from PD modeling alone=11.1 ng/mL (95% confidence interval (CI)=10.1 to 12.1); while that derived from combined PK-PD modeling=8.63 ng/mL (95% CI=7.75 to 9.51)). This finding suggests that PK-PD modeling is required to obtain reliable prediction of brain occupancy by antipsychotics.
Authors:
Euitae Kim; Oliver D Howes; Bo-Hyung Kim; Jae Min Jeong; Jae Sung Lee; In-Jin Jang; Sang-Goo Shin; Federico E Turkheimer; Shitij Kapur; Jun Soo Kwon
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Publication Detail:
Type:  Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-12-21
Journal Detail:
Title:  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism     Volume:  32     ISSN:  1559-7016     ISO Abbreviation:  J. Cereb. Blood Flow Metab.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-04-04     Completed Date:  2012-05-25     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  8112566     Medline TA:  J Cereb Blood Flow Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  759-68     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Antipsychotic Agents / administration & dosage,  pharmacokinetics*
Brain / metabolism*,  radiography*
Humans
Male
Models, Theoretical*
Piperazines / administration & dosage,  pharmacokinetics*
Positron-Emission Tomography*
Quinolones / administration & dosage,  pharmacokinetics*
Receptors, Dopamine / metabolism*
Time Factors
Grant Support
ID/Acronym/Agency:
G0701748//Medical Research Council; MC_U120085814//Medical Research Council; MC_U120097115//Medical Research Council; U.1200.04.007.00001.01//Medical Research Council
Chemical
Reg. No./Substance:
0/Antipsychotic Agents; 0/Piperazines; 0/Quinolones; 0/Receptors, Dopamine; 82VFR53I78/aripiprazole
Comments/Corrections

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