Physiologically Based Modeling Approach to Predict Dopamine D2 Receptor Occupancy of Antipsychotics in Brain: Translation From Rat to Human.

ABSTRACT: Receptor occupancy (RO) is a translational biomarker for assessing drug efficacy and safety. We aimed to apply a physiologically based pharmacokinetic (PBPK) modeling approach to predict the brain dopamine D2 RO time profiles of antipsychotics. Clozapine and risperidone were modeled together with their active metabolites, norclozapine and paliperidone, First, in PK-Sim a rat PBPK model was developed and optimized using literature plasma PK data. Then, blood-brain barrier parameters including the expression and efflux transport kinetics of P-glycoprotein were optimized using literature microdialysis data on brain extracellular fluid (brainECF), which were further adapted when translating the rat PBPK model into the human PBPK model. Based on the simulated drug and metabolite concentrations

SUBMITTER: Wong YC 

PROVIDER: S-EPMC6590357 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature