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

Abstract

In vivo characterization of the brain pharmacokinetics of novel compounds provides important information for drug development decisions involving dose selection and the determination of administration regimes. In this context, the compound-target affinity is the key parameter to be estimated. However, if compounds exhibit a dynamic lag between plasma and target bound concentrations leading to pharmacological hysteresis, care needs to be taken to ensure the appropriate modeling approach is used so that the system is characterized correctly and that the resultant estimates of affinity are correct. This work focuses on characterizing different pharmacokinetic models that relate the plasma concentration to positron emission tomography outcomes measurements (e.g., volume of distribution and target occupancy) and their performance in estimating the true in vivo affinity. Measured (histamine H3 receptor antagonist-GSK189254) and simulated data sets enabled the investigation of different modeling approaches. An indirect pharmacokinetic-receptor occupancy model was identified as a suitable model for the calculation of affinity when a compound exhibits pharmacological hysteresis.

Receptor Occupancy of the -Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050

“…An initial analysis found a trend (P 5 0.09) toward different IC 50 values at t max and 24 hours. For further evaluation, indirect effect models (Abanades et al, 2011;Salinas et al, 2013) could be applied; these models characterize hysteresis in the PK-RO curve by modeling the blood-brain exchange and binding kinetics of the drug.…”

Mechanistic Multilayer Quantitative Model for Nonlinear Pharmacokinetics, Target Occupancy and Pharmacodynamics (PK/TO/PD) Relationship of D-Amino Acid Oxidase Inhibitor, TAK-831 in Mice

“…Since the absorption phase was not clearly observed, TAK-831 dosage was dealt with as a direct injection into plasma PK compartment. The PK/TO relationship of TAK-831 was described by mechanistic binding kinetics model ( 18 ), which accounts for the association and dissociation rates to the target enzyme in relation to the plasma concentration of TAK-831 assuming a rapid equilibrium between plasma and brain free concentrations. Additional simulation was performed utilizing estimated unbound cerebellum concentrations of TAK-831 as PK input for TO model analysis to support this assumption ( Supplementary information ).…”

Imaging in Central Nervous System Drug Discovery

“…can be readily estimated from such experiments. If these conditions are not met and the drug kinetics are "Indirect" then improved experimental designs are required which involve the measurement of occupancy at different time points post-administration and varying doses [25][26][27].…”

“…measured from a SD PET study will translate to an RD study and only RD PK is needed. However, if the relationship is Indirect then one either needs to measure the occupancy from a RD PET study or predict it from the SD PET study using an appropriate mathematical model [25,26]. Under such conditions, and assuming the administration of the drug does not change the target affinity for either the drug or the radioligand, the !"…”