Permeability benchmarking: guidelines for comparing in silico, in vitro, and in vivo measurements

Abstract

Permeability is a measure of the degree to which cellscan transport molecules across biological barriers. Units ofpermeability are distance per unit time (typically cm/s), whereaccurate measurements are needed to define drug delivery inhomeostasis and to model dysfunction occurring during disease. This perspective offers a set of community-led guidelines tobenchmark permeability data across multidisciplinary approachesand different biological contexts. First, we lay out the analyticalframework for three methodologies to calculate permeability: insilico assays using either transition-based counting or theinhomogeneous-solubility diffusion approaches, in vitro permeabilityassays using cells cultured in 2D or 3D geometries, and in vivo assaysutilizing in situ brain perfusion or multiple time-point regressionanalysis. Then, we demonstrate a systematic benchmarking of in silico to both in vitro and in vivo, depicting the ways in which eachbenchmarking is sensitive to the choices of assay design. Finally, we outline seven recommendations for best practices inpermeability benchmarking and underscore the significance of tailored permeability assays in driving advancements in drug deliveryresearch and development. Our exploration encompasses a discussion of “generic” and tissue-specific biological barriers, includingthe blood−brain barrier (BBB), which is a major hurdle for the delivery of therapeutic agents into the brain. By addressingchallenges in reconciling simulated data with experimental assays, we aim to provide insights essential for optimizing accuracy andreliability in permeability modeling.

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ORCID for Ian Galea: orcid.org/0000-0002-1268-5102

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