The Role of Blood-Brain Barrier Studies in the Pharmaceutical Industry

Abstract

The blood-brain barrier (BBB) remains one of the greatest challenges for the discovery and development of treatments for CNS disorders, which to this day remains one of the riskiest disease areas in terms of clinical success rates. Although the BBB is currently seen predominantly as a permeability obstacle for CNS drug delivery, it is becoming increasingly clear that the BBB has many more implications for the pharmaceutical industry impacting on CNS pharmacology and pathology, CNS pharmacokinetics and pharmacodynamics, and adverse CNS effects, to name but a few areas. The present review does not intend to summarize the activities in the field of BBB research per se, which has been accomplished by a number of excellent recent reviews, but instead to provide an overview of the role of BBB studies from a pharmaceutical industry perspective. This review will elaborate on the specific needs in terms of BBB-related issues across the different drug discovery and development phases, i.e. target identification and validation, lead generation and optimization, candidate selection and profiling, preclinical development and clinical studies. The specific approaches taken will be discussed in terms of specific requirements, questions to be asked, feasibility, interpretability, and impact. It becomes clear that few of the existing BBB models fully meet the requirements of the industrialized drug discovery process, highlighting the need for an array of new or modified tools and approaches that are more effective in helping make decisions which are more specifically tailored to the various stages of the lengthy process from target to the clinic. In looking at the numerous ongoing activities in the area of BBB research from the drug discovery and development point of view, an attempt has been made to place a stronger emphasis on the applicability of particular techniques and approaches, to identify gaps and areas for future activities. In order to materialize the considerable knowledge gained in recent years, the review is intended to foster an increased awareness of the need to better integrate basic academic research with the specific requirements of the pharmaceutical industry for the search of effective and safe new CNS medicines.

Quantitative Investigation of the Brain-to-Cerebrospinal Fluid Unbound Drug Concentration Ratio under Steady-State Conditions in Rats Using a Pharmacokinetic Model and Scaling Factors for Active Efflux Transporters

“…It was also reported that it is only 2-to 6-fold larger than the apical and basal surface areas, respectively, of the choroid plexus in rats (Keep and Jones, 1990). The fitted parameter A was of the same order of magnitude as the reported value (Pardridge et al, 1981;De Lange, 2004;Reichel, 2006). The method used for estimating PS 1 barely affected the fitted parameters B, C, and D. To verify parameters B and C, scaling factors for P-gp-and Bcrp-mediated efflux, in vivo PS P-gp and PS Bcrp of flavopiridol, the brain penetration of which is limited by both P-gp and Bcrp, were calculated using the in vitro CFR transport activities of P-gp and Bcrp, and fitted parameters B and C. In vivo PS P-gp was 4.3-fold higher than PS Bcrp .…”

“…Assuming an equal passive permeability per unit surface area across the BBB and BCSFB, parameter A corresponds to the difference in the surface area for drug penetration from the blood circulation into the brain and CSF. The surface area of capillaries at the BBB is 5000-fold larger than that at the BCSFB (Pardridge et al, 1981;De Lange, 2004;Reichel, 2006). It was also reported that it is only 2-to 6-fold larger than the apical and basal surface areas, respectively, of the choroid plexus in rats (Keep and Jones, 1990).…”

Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

“…This latter consideration is especially important for compounds like BQCA which require blood-brain barrier (BBB) permeability to reach their therapeutic target; a modified version of the Rule of Five suggests a MW < 450 Da for BBB passage. 95 The multiple points for diversification on the BQCA scaffold have since resulted in a plethora of SAR studies that have generated a wide variety of analogues, some of which display substantial improvement on the characteristics of the parent compound. It is important to note however that all subsequent BQCA analogues described here were evaluated in only one functional assay against a single orthosteric ligand concentration, equating compound potencies to the EC 50 (point of inflection) of the compound's CRC in the presence of an EC 20 of ACh at human M 1 mAChR-expressing CHO cells using FLIPR calcium mobilization assays.…”

Drug Discovery Methods for Studying Brain Drug Delivery and Distribution

“…Gabapentin is a substrate of the L-type amino acid transporter, which explains the observed active uptake into the cells (Wang and Welty 1996;Friden et al 2011) The identification and selection of drug candidates with "acceptable brain penetration" has typically been based on predefined cutoff values for K p,brain (BB or often logBB); however, these vary between groups/companies. For instance, logBB = 0.3 (K p,brain = 2) has often been used as the cutoff point for NCE penetration of the BBB (Reichel 2006). Another approach uses an arbitrary cutoff point for K p,brain of greater than unity (Kalvass et al 2007a;Padowski and Pollack 2011a).…”