Abstract

Translation of central nervous system receptor occupancy from animal models to humans has been elusive for many theraprutic targets. However, this may represent a valuable link to clinical efficacy of drugs acting within the brain and spinal cord. The introduction of positron emission tomography (PET) has marked a significant noninvasive advance in determination of target engagement in the central nervous system. Pharmacokinetic/ pharmacodynamic (PK/PD) modeling represents a valuable tool to translate ex vivo receptor occupancy from relevant animal models to humans. While PK properties usually are reasonably scaled across species using standard allometric principles, PD properties related to receptor occupancy are usually species-independent. The translational value and applicability of PK/PD approaches is more directly evident when comparable modeling assumptions and mathematical model structures are employed across experiments and analyses. The purpose of this letter is to review the basic principles of PK/PD analysis of receptor occupancy determined using noninvasive PET imaging, and first principles of allometric PK scaling and PD prediction based on animal data. We also provide a case study of PK/PD analysis showcasing the importance of PK/PD model assumptions in predicting receptor occupancy in humans based on data from animal models using data from the area of pain management.