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Physiologically Based Pharmacokinetic Modelling of Drug Penetration Across the Blood–Brain Barrier—Towards a Mechanistic IVIVE-Based Approach

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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.

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Authors and Affiliations

  1. Centre de Pharmacocinétique et Métabolisme, Groupe de Recherche Servier, Orléans, France

    Kathryn Ball, François Bouzom & Bernard Walther

  2. Neuropsychopharmacologie des addictions (CNRS UMR 8206), Faculté de Pharmacie, Université Paris Descartes, Paris, France

    Jean-Michel Scherrmann & Xavier Declèves

  3. INSERM U705, Neuropsychopharmacologie des addictions, Paris, France

    Jean-Michel Scherrmann & Xavier Declèves

  4. Technologie Servier, 25/27 Rue Eugene Vignat, 45000, Orléans, France

    François Bouzom

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  1. Kathryn Ball
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  2. François Bouzom
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Correspondence to François Bouzom.

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Ball, K., Bouzom, F., Scherrmann, JM. et al. Physiologically Based Pharmacokinetic Modelling of Drug Penetration Across the Blood–Brain Barrier—Towards a Mechanistic IVIVE-Based Approach. AAPS J 15, 913–932 (2013). https://doi.org/10.1208/s12248-013-9496-0

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