Pharmacokinetic Concepts in Brain Drug Delivery

Abstract

This chapter presents the pharmacokinetic principles of blood-brain barrier (BBB) transport and the intra-brain distribution of drugs in order to provide a basis for understanding drug delivery to the brain from a clinically relevant perspective. The most important concentrations to measure when determining drug distribution are those of the unbound drug, because it is the unbound drug that causes the pharmacological effect by interacting with the target. Therefore, this chapter also discusses the pharmacokinetic basis, the kind of information provided, and the in vivo relevance of the methods used to obtain reliable, therapeutically useful estimates of brain drug delivery. The main factors governing drug distribution to the brain are the permeability of the BBB to the drug (influx clearance), the extent of nonspecific binding to brain tissue, and the efflux clearance of the drug. The ratio of the influx and efflux clearances provides an estimation of the extent of drug equilibration across the BBB, described by K p,uu,brain . This parameter is important, as active uptake and/or efflux transporters influence the absolute brain concentrations of unbound drug in relation to those in plasma. The advantage of using K p,uu,brain during the drug discovery process lies in its ability to predict the potential success of drugs intended for action within the brain or, conversely, of those with few or no side effects in the brain.

Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates

“…Three main barrier layers are considered to separate the blood and the CNS: the endothelium of the brain microvessels, the epithelium of the choroid plexus, and the epithelium of the arachnoid mater 51. Uptake of G3‐DSA was easily detectable in cells surrounding blood vessels ( Figure 7 A).…”

Probing the extracellular diffusion of antibodies in brain using in vivo integrative optical imaging and ex vivo fluorescence imaging

“…It is very important to accurately characterize and understand the factors governing the in vivo diffusion behavior of proteins such as IgG because of their potential use as centrally applied therapeutics[13, 15]. Our experimental value for D* represents the first such measurement using a method focused exclusively on IgG antibody diffusion in brain ECS in vivo .…”

“…Several IgGs have already been in clinical trials for Alzheimer's disease, but a number of these have failed to meet their primary endpoints despite promising pre-clinical results; the precise reasons for these failures remain unclear (e.g. they may include inadequate selection of potentially responsive patient populations[14]), but a major factor is likely associated with the challenge of achieving adequate delivery to sites of action within the brain[15]. Strategies to address this delivery challenge include systemic approaches that utilize endogenous receptor-mediated transcytosis systems at the blood-brain barrier[16] or central approaches such as administering antibodies intraventricularly or intrathecally so they may travel along with the CSF circulation[13].…”

A Review on Nasal Drug Delivery System and Its Contribution in Therapeutic Management

“…Both controlled release and conventional release drug delivery are possible through nasal route. The requirement of the pharmaceutical excipients depends on the mode of drug delivery, that is, local or systemic drug delivery [59][60][61][62][63]. A wide range of nasal formulations are available and many studies have been done so far, some of these delivery systems and their key features are summarized below.…”

“…Nose drops can be delivered with a squeezy or by a pipette a bottle. These pharmaceuticals formulations are often recommended for treating local conditions, which include suffering some challenges such as microbial growth, mucosal dysfunction, and non-specific loss of the nose or lower back [61][62][63][64][65][66]. The featured disadvantage of this system is the lack of the dose precision, and therefore, nasal drops may not be useful for prescription products.…”