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.

Adjunctive aripiprazole in the treatment of risperidone-induced hyperprolactinemia: A randomized, double-blind, placebo-controlled, dose–response study

“…Dopamine D2 antagonists, such as risperidone, bind to D2 receptors in the pituitary gland and lead to the release of prolactin by the lactotroph cells. Aripiprazole, a potent partial agonist of the dopamine D2 receptors (Kessler, 2007), has a greater affinity for the D2 receptor than risperidone with central D2 receptor occupancy of approximately 70% at a dose of 2 mg/day (Kegeles et al, 2008;Kim et al, 2012). The partial agonist property means that, in the presence of dopamine hypoactivity, as induced by risperidone, aripiprazole will function as a dopamine agonist with roughly 30% intrinsic activity at postsynaptic receptors, restoring tonic inhibition to anterior pituitary lactotroph cells (Grunder et al, 2003), thereby decreasing serum prolactin levels.…”

Understanding the Hysteresis Loop Conundrum in Pharmacokinetic / Pharmacodynamic Relationships

“…However, besides the limited access of drugs to the site of action the presence of slow receptor kinetics are recognized as one of the main causes of counter-clockwise hysteresis [111]. It has been reported that in the case of anti-psychotic drugs they need to traverse not only the BBB but also the transporters that reside in this barrier [12]. The rate at which drugs bind to the receptor (k on ) and the rate at which it dissociates from a receptor (k off ) determine the kinetics of a drug such as in the case of anti-psychotic drugs and their relationship with the dopamine D 2 receptor [12].…”

“…It has been reported that in the case of anti-psychotic drugs they need to traverse not only the BBB but also the transporters that reside in this barrier [12]. The rate at which drugs bind to the receptor (k on ) and the rate at which it dissociates from a receptor (k off ) determine the kinetics of a drug such as in the case of anti-psychotic drugs and their relationship with the dopamine D 2 receptor [12]. For these types of drugs the k on values show low variability for various drugs, but the k off can vary within a 1000-fold range [112].…”

Molecular Imaging PET and SPECT Approaches for Improving Productivity of Antipsychotic Drug Discovery and Development

“…PK-RO relationships obtained from mathematical models applied to phase I study data can be subsequently used to predict the dose or plasma concentration required to achieve a certain level of RO. In these PK-RO models, the use of C P is preferable to the use of doses, given the inter-subject variability usually shown for a certain dose and antipsychotic drug [83]. Knowing the pharmacodynamics of a drug (dose-C P relationship), doses can be inferred from the PK-PD models based on C P .…”