title: Predicting brain occupancy from plasma levels using PET: superiority of combining pharmacokinetics with pharmacodynamics while modeling the relationship.
abstract: 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.affiliation: Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Euitae
authors.initials: E
authors.lastname: Kim
authors.forename: Oliver D
authors.initials: OD
authors.lastname: Howes
authors.forename: Bo-Hyung
authors.initials: BH
authors.lastname: Kim
authors.forename: Jae Min
authors.initials: JM
authors.lastname: Jeong
authors.forename: Jae Sung
authors.initials: JS
authors.lastname: Lee
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: Federico E
authors.initials: FE
authors.lastname: Turkheimer
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
authors.forename: Jun Soo
authors.initials: JS
authors.lastname: Kwon
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068180:Aripiprazole; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008962:Models, Theoretical; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011859:Radiography; D011954:Receptors, Dopamine / Q000378:metabolism*; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D011954:Receptors, Dopamine; D000068180:Aripiprazole