CPSA Shanghai 2011
Changing Paradigm in Drug Discovery & Development:
East Meets West
April 13 - 16, 2011
Renaissance Shanghai Pudong Hotel
Shanghai, China
Abstract
Thursday PM - Parallel Session I
Human CNS Penetration: Can It Be Predicted from Preclinical Data?
Haojing Rong
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Inc., Cambridge, MA USA
Prediction of human CNS penetration plays a critical role in assessing the viability of CNS drug candidates and determining plasma exposure required for central efficacy. Therefore, significant amount of research have been conducted by the pharmaceutical R&D and the academic labs to better understand the factors in determining the CNS drug disposition.
Although various preclinical assays, e.g. in vitro P-gp assay, permeability assay, in vivo brain pharmacokinetic study in rodents and P-gp knockout mice, are routinely being used as screening tools to predict CNS penetration in human, the lack of comprehensive data sets, both preclinical and clinical, has limited efforts to evaluate the predictability of preclinical assays for human CNS penetration. To address this issue, a retrospective analysis was performed using thirty-two Pfizer proprietary compounds for which in vitro preclinical CNS pharmacokinetic and human CSF pharmacokinetic data, and/or receptor occupancy data utilizing Positron Emission Tomography were available. The predictability of individual preclinical assay as well as combination of in vitro and in vivo assays was assessed using correlation with human CNS penetration based on human CSF exposure or receptor occupancy. The use of plasma and CSF exposure as surrogate exposures in human for CNS target were also evaluated.
The results has indicated that preclinical investigations are useful to predict CNS penetration in human and able to recommend appropriate surrogate for CNS target exposure in human.
Haojing Rong is a Senior Principle Scientist in the Pharmacokinetics, Dynamics, and Drug Metabolism Department at Pfizer in Cambridge, MA. She earned her Ph.D. at Faculty of Pharmaceutical Science of Ghent University in Belgium in 2000. After graduation, she started her career as a Research Scientist at Pharmacokinetic and Drug Metabolism Department of Amgen, Thousand Oaks, CA, followed by a Research Fellow at Drug Metabolism and Pharmacokinetic Department at Merck, San Diego, CA. She was founding member of Amira Pharmaceuticals, San Diego, CA and built up the DMPK group at Amira prior to joining Pfizer in 2006. She had been a PDM principle investigator for Oncology and Neuroscience at Pfizer Groton site from 2006 to 2010. Recently, she is a PDM principle investigator for Orphan and Genetic Disease Research Unit at Cambridge, MA. Her interest and expertise include ADME knowledge integration for both small molecule and biotherapeutics, prediction of human pharmacokinetics and drug interactions using modeling and simulations, and applying integrated PK/PD modeling approach to drug discovery projects. She has authored and co-authored many research papers and has given invited oral presentations at many scientific conferences.