Estimation of target occupancy in repeated dosing design studies using positron emission tomography: Biases due to target upregulation

Positron emission tomography (PET) has become indispensable in the quantification of target engagement by brain targeting medications. The relationship between the drug plasma concentration (or drug dose administered) and target occupancy determined during a PET occupancy study has provided valuable information for the assessment of novel pharmaceuticals in the early phases of drug development. Such information is also critical for the understanding of the mechanisms of action and side-effect profile of approved medication commonly used in the clinic. Occupancy studies conducted following repeated drug dosing (RD) can produce systematic differences from those conducted following single drug dose (SD), differences that have not been adequately explored. We have hypothesised that when differences are observed between RD and SD studies, they are related to changes in target density induced by repeated drug accumulation. We have developed a modified occupancy model to account for potential changes in target density and tested it on a sample dataset. We found that target upregulation can parsimoniously explain the differences in drug affinity estimated in SD and RD studies. Our findings have implications for the interpretation of RD occupancy data in the literature and the relationship between specific target occupancy levels and drug efficacy and tolerability.