Translational Model-Informed Dose Selection for a Human Positron Emission Tomography Imaging Study of JNJ-54175446, a P2X7 Receptor Antagonist.

ABSTRACT: Positron emission tomography (PET) provides useful information in target engagement or receptor occupancy in the brain for central nervous system (CNS) drug development, however, dose selection for human PET studies is challenging and largely empirical. Here, we describe a translational pharmacokinetic/pharmacodynamic (PK/PD) modeling work to inform dose selection for a human PET study of JNJ-54175446, a CNS-penetrating P2X7 receptor antagonist. Models were developed using data on monkey brain occupancy and plasma drug exposures from a monkey PET study and early human clinical studies that provided data on drug exposures and human ex vivo-stimulated peripheral interleukin (IL)-1β release. The observed plasma PK of JNJ-54175446 in human was adequately described by a one-compartment model wi

SUBMITTER: Xu Y 

PROVIDER: S-EPMC7070800 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature