Adaptive-Optimal Design in PET Occupancy Studies

Abstract

Positron emission tomography (PET) is an imaging technique that is used to investigate ligand-receptor binding in the living brain and to determine the time course of plasma concentration/receptor occupancy (RO). The purpose of this work was to demonstrate the added value of an adaptive-optimal design for PET scan timings and dose selection over traditional study designs involving fixed or educated selections of timings and doses. A k(on)-k(off) model relating plasma concentration to PET data was applied to generate the simulated data. Optimization was performed on scanning timings and doses using the D-optimality criterion. Optimal designs as applied to scanning timings provided unbiased estimates and improved the accuracy of results relative to those of fixed and educated designs. Optimization of both timings and dose provided improvements in accuracy and precision when the initial dose selection was noninformative regarding the time course of RO. These results indicate that adaptive-optimal designs can provide an efficient experimental design for RO studies using PET, by minimizing the number of subjects required and maximizing information related to the plasma concentration-RO relationship.

Kinetic Analysis of Drug–Target Interactions with PET for Characterization of Pharmacological Hysteresis

“…Simulations investigating the impact of study duration (T d ) on the accuracy of K d estimates revealed that the indirect model was able to accurately recover the K d unless the kinetics of the compound were particularly slow or T d was too short such the TOC appeared irreversible with respect to the plasma concentration. It should be noted that the choice of doses and times at which the TOC is sampled has an impact on the precision of the affinity estimates 23 but that this should not change these general findings. In contrast, the direct model repeatedly failed to recover the true K d value (except for artifactual cases explained previously).…”

Monoamine Transporter Occupancy of a Novel Triple Reuptake Inhibitor in Baboons and Humans Using Positron Emission Tomography

“…The time of PET scan 2 for the first two subjects was approximately 2 hours postdose (FTIH data indicated a plasma time of maximal concentration of 1.5-3 hours postdose for GSK1360707), and time of PET scan 3 was approximately 12 hours postdose based on observed human pharmacokinetics. For subsequent subjects, the dose (of GSK1360707) and timing of PET scans 2 and 3 were adjusted after review of the preceding subjects' data to ensure an adequate sampling of the TOC using an adaptive design approach (Zamuner et al, 2010;Abanades et al, 2011). Subjects returned for a follow-up visit approximately 7 to 14 days after their last dose of study medication.…”

Positron emission tomography molecular imaging for drug development

“…Adaptive designs that use information gained from each single observation to improve the selection of the subsequent dose can optimize the efficiency of a study [16]. The less prior knowledge concerning dosing that is available, the greater the potential efficiency gains with adaptive designs [16].…”