In Vitro to In Vivo Extrapolation Linked to Physiologically Based Pharmacokinetic Models for Assessing the Brain Drug Disposition

Abstract

Drug development for the central nervous system (CNS) is a complex endeavour with low success rates, as the structural complexity of the brain and specifically the blood-brain barrier (BBB) poses tremendous challenges. Several in vitro brain systems have been evaluated, but the ultimate use of these data in terms of translation to human brain concentration profiles remains to be fully developed. Thus, linking up in vitro-to-in vivo extrapolation (IVIVE) strategies to physiologically based pharmacokinetic (PBPK) models of brain is a useful effort that allows better prediction of drug concentrations in CNS components. Such models may overcome some known aspects of inter-species differences in CNS drug disposition. Required physiological (i.e. systems) parameters in the model are derived from quantitative values in each organ. However, due to the inability to directly measure brain concentrations in humans, compound-specific (drug) parameters are often obtained from in silico or in vitro studies. Such data are translated through IVIVE which could be also applied to preclinical in vivo observations. In such exercises, the limitations of the assays and inter-species differences should be adequately understood in order to verify these predictions with the observed concentration data. This report summarizes the state of IVIVE-PBPK-linked models and discusses shortcomings and areas of further research for better prediction of CNS drug disposition.

EFSA Pilot Project on New Approach Methodologies (NAMs) for Tebufenpyrad Risk Assessment. Part 1. Development of Physiologically‐Based Kinetic (PBK) Model Coupled With Pulmonary and Dermal Exposure

“…These steps are:  SPATIAL DISTRIBUTION INTO THE BRAIN. The spatial distribution is not really taken into account in the already cited PBK review (Murata et al 2022) dedicated to CNS where brain is schematically divided into cerebro-spinal fluid, brain extracellular fluid and brain intracellular fluid. That is why, some of the articles cited in the review (Murata et al 2022) have been included in Annex A, focusing on anatomical structure and supplementing this focus with an article (Vendel et al, 2019;2020b;2020a) that considers the brain in three dimensions with binding but still without precise anatomical division.…”

“…The spatial distribution is not really taken into account in the already cited PBK review (Murata et al 2022) dedicated to CNS where brain is schematically divided into cerebro-spinal fluid, brain extracellular fluid and brain intracellular fluid. That is why, some of the articles cited in the review (Murata et al 2022) have been included in Annex A, focusing on anatomical structure and supplementing this focus with an article (Vendel et al, 2019;2020b;2020a) that considers the brain in three dimensions with binding but still without precise anatomical division. Indeed, the structure of the brain is very heterogeneous (Bourasset et al 2021), which has prevented the scientific community, even until today, from quantitatively predicting the spatial distribution of a xenobiotic in the different regions and tissues of this organ.…”

“…This is the most known step(Silva-Adaya et al, 2021) and a recent review(Murata et al 2022) surveyed CNS-dedicated PBK models with the most advanced ones linking IVIVE to PBK to focus on BBB permeability in relation to transporters. According to QSAR predictions made from its chemical structure on the webtool SwissADME(Daina et al, 2017) (http://www.swissadme.ch/index.php, request issued the 24th of June 2020), Tebufenpyrad crosses passively the BBB without efflux by Pgp although the very high protein binding works against this passage.…”

Predicting transporter mediated drug–drug interactions via static and dynamic physiologically based pharmacokinetic modeling: A comprehensive insight on where we are now and the way forward

“…These challenges can be attributed to the scarce availability of brain microvessels tissue, which is used to quantitate the absolute transporter abundance and also due to the large unexplained variability observed. Depending on the question to be addressed, the complexity of the model also varies from empirical, semi-mechanistic to a full PBPK model, thus demanding more and more quality and reliable compound and systems data (Murata et al, 2022). IV, or modified release formulations) can help identify or validate the model with regard to the transporter impact at absorption, the distribution level, or on the saturation kinetics.…”

Special issue on applications of in vitro, in vivo, and modeling and simulation tools for central nervous system drug disposition

“…P‐gp and BCRP protein expression data at the blood–brain barrier have been well‐documented. This information enables development of PBPK (physiologically‐based pharmacokinetic) models to simulate drug concentration–time profiles in the brain (Murata et al., 2022). PBPK modeling is becoming a valuable tool in preclinical and clinical study design and regulatory review (Grimstein et al., 2019; Zhang et al., 2020).…”