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

This special issue of Biopharmaceutics and Drug Disposition is a collection of articles intended to provide new insights into recent developments of in silico, in vitro, and in vivo tools to advance our understanding of CNS (central nervous system) drug disposition. Over the last decades, great progress has been made in the field to enable effective CNS drug design and delivery. Here, a few areas of the advances are highlighted. Unbound drug concentration in the brain, rather than the total brain drug concentration, has been widely recognized as the driver for in vivo efficacy (Liu et al., 2014; Smith et al., 2010). Critical factors influencing the rate and extent of brain penetration have been identified (Di & Kerns, 2015; Di et al., 2013; Hammarlund‐Udenaes et al., 2008). Passive permeability across the blood–brain barrier and plasma protein binding are key parameters that control the rate of brain uptake (Di et al., 2020; Trapa et al., 2016). On the other hand, P‐gp (P‐glycoprotein) and BCRP (breast cancer resistance protein) are the most important efflux transporters limiting the extent of brain exposure (Di et al., 2013; Loryan et al., 2022; Trapa et al., 2016). These insights help to develop effective design strategies to enhance or limit brain exposure in order to maximize CNS efficacy or minimize central toxicity. P‐gp and BCRP efflux transporters at the blood–brain barrier play critical roles in limiting brain penetration of many drug candidates. Quantification of transporter proteins at the blood–brain barrier has been a major breakthrough in the past decade (Al Feteisi et al., 2018; Al‐Majdoub et al., 2019; Bao et al., 2020; Billington et al., 2019; Gomez‐Zepeda et al., 2019; Hoshi et al., 2013; Ohtsuki et al., 2013; Sato et al., 2021; Shawahna et al., 2011; Storelli et al., 2021; Uchida et al., 2011, 2020). 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). High‐throughput screening assays using P‐gp and BCRP transfected cell lines (e.g. MDR1‐MDCK [multidrug resistance 1— Madin‐Darby canine kidney cell line], BCRP‐MDCK) have been broadly implemented in the pharmaceutical industry to measure efflux ratios of drug candidates. These data are widely applied by medicinal chemists to guide drug design in order to minimize efflux transport and enhance brain penetration. Quality cell lines with high transport expression levels are key to assay sensitivity for identification of efflux transporter substrates (Feng et al., 2019). In practice, brain endothelial cell culture systems are not commonly used in drug discovery to evaluate CNS drug disposition, as they are less robust, more variable, costly, and too complex to be implemented as standard assays (Loryan et al., 2022). Minimal species differences of substrate affinity for P‐gp and BCRP transporters have been reported (Feng et al., 2008, 2019). For P‐gp and BCRP substrates, translation from in vitro and preclinical species data to human in vivo brain exposure has made significant progress (Feng et al., 2018; Patel et al., 2021; Trapa et al., 2016, 2019). In vivo neuro‐PK (pharmacokinetics) studies have become standard practices to measure brain exposure in preclinical species (Di et al., 2013; Di & Kerns, 2015). In vivo data are highly informative to help develop IVIVE (in vitro–in vivo extrapolation) on brain penetration and predict human brain exposure. Cassette dosing can effectively increase throughput and reduce the cost of neuro‐PK studies (Liu et al., 2012). Efflux transporter knockout animals (e.g. Mdr1a‐/‐, Bcrp‐/‐) are available for mechanistic studies to understand the impact of these transporters on brain penetration (Kido et al., 2022). PET (positron emission tomography) and other imaging techniques have provided great insights of brain exposure in animals and humans (Hernandez‐Lozano et al., 2021). This valuable data can be used to validate the predictions of human brain exposure from in vitro and in vivo animal data, as well as PBPK modeling and simulation. It is an exciting era to witness the remarkable development of delivering therapeutic drugs of new modalities (e.g. proteins and oligonucleotides) to the brain for treatment of CNS diseases. Neuro‐PK studies now have been extended to evaluate brain penetration beyond small molecules. As large molecules tend to have low brain penetration, removing the residual blood from the capillaries in the brain tissue is essential in order to generate reliable data (Noh et al., 2022). Brain tissue binding enables the calculation of unbound drug concentration in the brain when used in conjunction with neuro‐ PK. Brain tissue homogenate is most commonly used for brain tissue binding studies compared to using brain slices (Loryan et al., 2022). Binding to brain tissue has been shown to be species‐independent (Di et al., 2011; Ryu et al., 2020). Brain tissue from a single species, such as rat, can be used as a surrogate for brain tissue binding