Physiologically Based Pharmacokinetic Modelling of Drug Penetration Across the Blood–Brain Barrier—Towards a Mechanistic IVIVE-Based Approach
Journal Title: The AAPS Journal - Year 2013, Vol 15, Issue 4
Abstract
Predicting the penetration of drugs across the human blood–brain barrier (BBB) is a significant challenge during their development. A variety of in vitro systems representing the BBB have been described, but the optimal use of these data in terms of extrapolation to human unbound brain concentration profiles remains to be fully exploited. Physiologically based pharmacokinetic (PBPK) modelling of drug disposition in the central nervous system (CNS) currently consists of fitting preclinical in vivo data to compartmental models in order to estimate the permeability and efflux of drugs across the BBB. The increasingly popular approach of using in vitro–in vivo extrapolation (IVIVE) to generate PBPK model input parameters could provide a more mechanistic basis for the interspecies translation of preclinical models of the CNS. However, a major hurdle exists in verifying these predictions with observed data, since human brain concentrations can’t be directly measured. Therefore a combination of IVIVE-based and empirical modelling approaches based on preclinical data are currently required. In this review, we summarise the existing PBPK models of the CNS in the literature, and we evaluate the current opportunities and limitations of potential IVIVE strategies for PBPK modelling of BBB penetration.
Authors and Affiliations
Kathryn Ball, François Bouzom, Jean-Michel Scherrmann, Bernard Walther, Xavier Declèves
Keywords
Related Articles
- EP ID EP681151
- DOI 10.1208/s12248-013-9496-0
- Views 69
- Downloads 0
Conformational Analysis of Therapeutic Proteins by Hydroxyl Radical Protein Footprinting
The online version of this article (doi:10.1208/s12248-012-9336-7) contains supplementary material, which is available to authorized users.
Atenolol quantification in human plasma by high-performance liquid chromatography: Application to bioequivalence study
An accurate, precise, and sensitive high-performance liquid chromatography (HPLC) assay was developed for the determination of atenolol in human plasma samples to compare the bioavailability of 2 atenolol tablet (50 mg)...
Marketplace Analysis of Conjugated Estrogens: Determining the Consistently Present Steroidal Content with LC-MS
The online version of this article (doi:10.1208/s12248-015-9805-x) contains supplementary material, which is available to authorized users.
Monoamine Transporter Structure, Function, Dynamics, and Drug Discovery: A Computational Perspective
The online version of this article (doi:10.1208/s12248-012-9391-0) contains supplementary material, which is available to authorized users.
Modeling Testosterone Circadian Rhythm in Hypogonadal Males: Effect of Age and Circannual Variations
The objective of this study was to characterize the baseline circadian rhythm of testosterone levels in hypogonadal men. A total of 859 baseline profiles of testosterone from hypogonadal men were included in this analysi...