PT  - JOURNAL ARTICLE
AU  - Melhem, Murad
TI  - Translation of Central Nervous System Occupancy from Animal Models: Application of Pharmacokinetic/Pharmacodynamic Modeling
AID  - 10.1124/jpet.112.199794
DP  - 2013 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 2--6
VI  - 347
IP  - 1
4099  - http://jpet.aspetjournals.org/content/347/1/2.short
4100  - http://jpet.aspetjournals.org/content/347/1/2.full
SO  - J Pharmacol Exp Ther2013 Oct 01; 347
AB  - Translation of central nervous system receptor occupancy from animal models to humans has been elusive for many therapeutic targets. However, this may represent a valuable link to clinical efficacy for drugs acting within the brain and spinal cord. The introduction of positron emission tomography 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. Whereas 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 are more directly evident when comparable modeling assumptions and mathematical model structures are employed across experiments and analyses. The purpose of this article is to review the basic principles of PK/PD analysis of receptor occupancy determined using noninvasive positron emission tomography imaging and first principles of allometric PK scaling and PD prediction based on animal data. By use of the data from the area of pain management, 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.