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 53
- Downloads 0
Endocannabinoid metabolomics: A novel liquid chromatography-mass spectrometry reagent for fatty acid analysis
We have synthesized 4,4-dimethoxyoxazoline derivatives of several fatty acids associated with the endocannabinoid metabolome using tris(hydroxymethyl)aminomethane in a 1-step reaction by microwave irradiation. The deriva...
Dissolution Similarity Requirements: How Similar or Dissimilar Are the Global Regulatory Expectations?
The objective of this article is to compare and contrast the international expectations associated with the model-independent similarity factor approach to comparing dissolution profiles. This comparison highlights globa...
Biological Products for the Treatment of Psoriasis: Therapeutic Targets, Pharmacodynamics and Disease-Drug-Drug Interaction Implications
Psoriasis is a chronic inflammatory skin disease condition that involves altered expression of a broad spectrum of proinflammatory cytokines which are associated with activation of T cells and proliferation of keratinocy...
Optimization of chlorphenesin emulgel formulation
This study was conducted to develop an emulgel formulation of chlorphenesin (CHL) using 2 types of gelling agents: hydroxypropylmethyl cellulose (HPMC) and Carbopol 934. The influence of the type of the gelling agent and...
Role of animal models in the study of drug-induced hypersensitivity reactions
Drug-induced hypersensitivity reactions (DHRs) are a major problem, in large part because of their unpredictable nature. If we understood the mechanisms of these reactions better, they might be predictable. Their unpredi...