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

Ball, Kathryn; Bouzom, François; Scherrmann, Jean‐Michel; Walther, Bernard; Declèves, Xavier

doi:10.1208/s12248-013-9496-0

Cited by 45 publications

(45 citation statements)

References 131 publications

(119 reference statements)

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“…In future it should be possible to combine information from in vivo and in vitro studies (Ito et al 2011b , c ) with quantitative proteomics (Uchida et al , b , 2013 to generate data for PKPD and "physiologically based pharmacokinetic" (PBPK) modelling, and for prediction of human CNS free drug concentrations (Shawahna et al 2013 ), based on data including information generated in in vitro models from different species (Ball et al 2012 ). The ultimate aim will be to permit reliable in vitro-in vivo extrapolation (IVIVE) to human brain (Ball et al 2013 ).…”

Section: Transcriptomics Proteomics and Pkpd Modelling And In Vitro-mentioning

confidence: 99%

In Vitro Models of CNS Barriers

Abbott

Dolman

Yusof

et al. 2013

AAPS Advances in the Pharmaceutical Sciences Series

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This chapter reviews the history and modern applications of isolated preparations of the three main CNS barrier layers and cell culture preparations derived from them. In vitro models give valuable mechanistic information but also provide useful assay systems for drug discovery and delivery programmes. However, it is important to take into account practical issues including species differences and the degree to which the differentiated state of the in vivo barrier is retained. The range of models available is reviewed, with a critical evaluation of their strengths and weaknesses, and guidance in selecting and optimizing a suitable model for particular applications. New understanding of the unstirred water layers and paracellular leak pathway in in vitro preparations gives greater insights into the "intrinsic permeability" of the membrane, and a variety of techniques permit characterization of the transport systems and enzymes contributing to barrier function. Increasingly, aspects of CNS pathology are being modelled in cell culture, aiding the optimization of drug delivery regimes in pathological conditions. Chapter 6In Vitro Models of CNS Barriers IntroductionFrom the earliest demonstration of restricted exchange between the blood and the brain (Ehrlich 1885 ) leading to the modern understanding of the blood-CNS barriers, animal experiments and clinical observations have provided valuable information about the physiology and pathology of the barrier layers. However, obtaining mechanistic information from such studies at the cellular and molecular level is complex and time-consuming, and it is often diffi cult to obtain suffi cient spatial and temporal resolution. The situation was dramatically improved by the introduction of in vitro methods (reviewed in Joó 1992 ). Background and Early HistoryThe fi rst successful isolation of cerebral microvessels (Siakotos and Rouser 1969 ;Joó and Karnushina 1973 ) prepared the way for development of in vitro models of the blood-brain barrier (BBB), which have contributed to current understanding of its physiology, pharmacology and pathophysiology (reviewed in Joó 1992 ). Methods have also been developed for in vitro models of the choroid plexus and of the arachnoid epithelium (blood-CSF barrier, BCSFB). However, this proliferation of in vitro models and techniques causes problems for attempts at comparison between models and transferability of results obtained with different models, and makes it hard for scientists entering the fi eld to select an optimal model for their particular interests. This chapter gives an overview of the current status of the most widely used in vitro CNS barrier models, with an update on an earlier review (Reichel et al. 2003 ), and offers guidance in model selection for specifi c applications, including permeability assay for drugs and "new chemical entities" (NCEs). Isolated brain microvessels were the fi rst model system for studying the BBB in vitro, offering new opportunities to investigate physiological and pathological processes at...

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Section: Transcriptomics Proteomics and Pkpd Modelling And In Vitro-mentioning

confidence: 99%

In Vitro Models of CNS Barriers

Abbott

Dolman

Yusof

et al. 2013

AAPS Advances in the Pharmaceutical Sciences Series

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“…Recently, there has been an increasing focus on translational modelling approaches compared to the traditional practice of fitting model parameters to preclinical in vivo data [65,66]. IVIVE-PBPK models reported by Fenneteau et al [67] and Ball et al [68] demonstrate promising examples. This review has addressed imperative differences among various PBPK models in use, including details on brain compartmentalization and parameterization.…”

Section: Ivive-pbpk Model For the Central Nervous Systemmentioning

confidence: 99%

Utilizing in vitro transporter data in IVIVE-PBPK: an overview

Mallick

2017

ADMET DMPK

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<p class="ADMETabstracttext">In vitro-in vivo extrapolation (IVIVE) integrated in physiologically-based pharmacokinetic (PBPK) models have been increasingly used during drug discovery and development processes to predict human pharmacokinetic (PK) parameters. Drug transporters can influence drug pharmacokinetics and are key aspects contributing to the development of a successful drug. This review provides a snapshot of challenges or shortcomings of in vitro and in vivo techniques for understanding the contribution of drug transporters to a drug’s pharmacokinetics. The paper also describes the potential of IVIVE-PBPK models as prospective approaches to predict the role of drug transporters in drug discovery and development.</p>

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“…The model depicts reversible drug movement from (1) blood to heterogeneous (healthy and tumor) brain, (2) blood to cranial CSF, (3) brain to cranial CSF, (4) cranial CSF to spinal CSF, and then both CSF compartments back to blood. Abbreviations: PBPK, physiologically-based pharmacokinetics; BBB, blood-brain barrier; BTB, blood-tumor barrier; CSF, cerebrospinal fluid; CL, clearance; Q, flow rate.…”

Section: Figurementioning

confidence: 99%

“…CNS drug development is not only hampered by the dynamic influx/efflux transporter system at the BBB but also the relatively poor predictive validity of preclinical models, the lack of accepted biomarkers and/or surrogate measures of drug activity/response, and the limited effective strategies to assess drug exposures in the brain. PBPK modeling of the CNS provides the opportunity to predict relevant drug concentrations at the therapeutic target site, and IVIVE linked with PBPK is a strategy to quantitatively bridge in vitro and in vivo data to explore the key mechanisms dictating the pharmacokinetics and BBB penetration of the drug (2). …”

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confidence: 99%