Preclinical prediction of human brain target site concentrations: Considerations in extrapolating to the clinical setting
TL;DR: There is a plea follows for the need for more mechanistic understanding of the mechanisms involved in brain target site distribution, and the condition-dependent contributions of these mechanisms to ultimate drug effect.
About: This article is published in Journal of Pharmaceutical Sciences.The article was published on 2011-09-01. It has received 71 citations till now.
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TL;DR: A particular emphasis is placed on the interplay between the most critical physicochemical and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chemistry strategies toward molecules with optimal brain exposure.
Abstract: The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing molecules that can overcome this protection system and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochemical properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most critical physicochemical and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chemistry strategies toward molecules with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided.
383 citations
TL;DR: In vitro models, including non-cell based and cell-based models, and in vivo models are presented, with a particular emphasis on their methodological aspects and their contribution to the improvement of brain drug delivery strategies and drug transport across the blood-brain barrier is discussed.
229 citations
TL;DR: A better understanding of these regulatory pathways during development, in particular the signaling pathways triggered by oxidative stress and xenobiotics, may open new opportunities to therapeutic manipulation in view to improve or restore neuroprotective functions of the blood-brain interfaces in the context of perinatal injuries.
Abstract: The cerebral microvessel endothelium forming the blood-brain barrier (BBB) and the epithelium of the choroid plexuses forming the blood-CSF barrier (BCSFB) operate as gatekeepers for the CNS. Exposure of the vulnerable developing brain to chemical insults can have dramatic consequences for brain maturation and lead to life-long neurological diseases. The ability of blood-brain interfaces (BBIs) to efficiently protect the immature brain is therefore an important pathophysiological issue. This is also key to our understanding of drug entry into the brain of neonatal and pediatric patients. Nonspecific paracellular diffusion through BBIs is restricted early during development, but other neuroprotective properties of these interfaces differ between the developing and adult brains. This review focuses on the developmental expression and function of multispecific efflux transporters of the ABCB, ABCC, ABCG, SLC21, SLC22, and SLC15 families. These transporters play a key role in preventing brain entry of blood-borne molecules such as drugs, environmental toxicants, and endogenous metabolites, or else in increasing the clearance of potentially harmful organic ions from the brain. The limited data available for laboratory animals and human highlight transporter-specific developmental patterns of expression and function, which differ between BBIs. The BCSFB achieves an adult phenotype earlier than the BBB. Efflux transporters at the BBB appear to be regulated by various factors subsequently secreted by neural progenitors, and astrocytes during development. Their expression is also modulated by oxidative stress, inflammation, and exposure to xenobiotic inducers. A better understanding of these regulatory pathways during development, in particular the signaling pathways triggered by oxidative stress and xenobiotics, may open new opportunities to therapeutic manipulation in view to improve or restore neuroprotective functions of the BBIs in the context of perinatal injuries.
110 citations
Cites background from "Preclinical prediction of human bra..."
...These include protein binding, local cerebral capillary density and cerebral blood flow, intraparenchymal diffusion rate, movement by fluid flow along perivascular spaces and within ventricular and cisternal spaces, and CSF turnover (reviewed in Ghersi-Egea et al., 2009; Westerhout et al., 2011)....
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TL;DR: It is concluded that for acetaminophen, a model compound for passive transport into, within, and out of the brain, differences exist between the brain ECF and the CSF pharmacokinetics.
Abstract: One of the major challenges in the development of central nervous system (CNS)-targeted drugs is predicting CNS exposure in human from preclinical data. In this study, we present a methodology to investigate brain disposition in rats using a physiologically based modeling approach aiming at improving the prediction of human brain exposure. We specifically focused on quantifying regional diffusion and fluid flow processes within the brain. Acetaminophen was used as a test compound as it is not subjected to active transport processes. Microdialysis probes were implanted in striatum, for sampling brain extracellular fluid (ECF) concentrations, and in lateral ventricle (LV) and cisterna magna (CM), for sampling cerebrospinal fluid (CSF) concentrations. Serial blood samples were taken in parallel. These data, in addition to physiological parameters from literature, were used to develop a physiologically based model to describe the regional brain pharmacokinetics of acetaminophen. The concentration–time profiles of brain ECF, CSFLV, and CSFCM indicate a rapid equilibrium with plasma. However, brain ECF concentrations are on average fourfold higher than CSF concentrations, with average brain-to-plasma AUC0 − 240 ratios of 121%, 28%, and 35% for brain ECF, CSFLV, and CSFCM, respectively. It is concluded that for acetaminophen, a model compound for passive transport into, within, and out of the brain, differences exist between the brain ECF and the CSF pharmacokinetics. The physiologically based pharmacokinetic modeling approach is important, as it allowed the prediction of human brain ECF exposure on the basis of human CSF concentrations.
106 citations
Cites background from "Preclinical prediction of human bra..."
...The blood–brain transport is restricted by the presence of the BBB and the blood–CSF barrier (BCSFB), which is located at the choroid plexuses of the lateral, third, and fourth ventricles (3), as well as at the cisterna magna....
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...The brain is a dynamic multi-compartmental system, in which all processes of drug entry, within brain diffusion, metabolism, binding, and elimination determine actual CNS target site concentrations (3)....
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...It is known that unbound plasma concentrations may not necessarily represent the unbound brain concentrations available for target interaction, due to distributional mechanisms (3)....
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TL;DR: On the basis of a few advanced preclinical microdialysis based investigations it will be shown that the “Mastermind approach” has a high potential for the prediction of human CNS drug effects.
Abstract: Despite enormous advances in CNS research, CNS disorders remain the world’s leading cause of disability. This accounts for more hospitalizations and prolonged care than almost all other diseases combined, and indicates a high unmet need for good CNS drugs and drug therapies. Following dosing, not only the chemical properties of the drug and blood–brain barrier (BBB) transport, but also many other processes will ultimately determine brain target site kinetics and consequently the CNS effects. The rate and extent of all these processes are regulated dynamically, and thus condition dependent. Therefore, heterogenious conditions such as species, gender, genetic background, tissue, age, diet, disease, drug treatment etc., result in considerable inter-individual and intra-individual variation, often encountered in CNS drug therapy. For effective therapy, drugs should access the CNS “at the right place, at the right time, and at the right concentration”. To improve CNS therapies and drug development, details of inter-species and inter-condition variations are needed to enable target site pharmacokinetics and associated CNS effects to be translated between species and between disease states. Specifically, such studies need to include information about unbound drug concentrations which drive the effects. To date the only technique that can obtain unbound drug concentrations in brain is microdialysis. This (minimally) invasive technique cannot be readily applied to humans, and we need to rely on translational approaches to predict human brain distribution, target site kinetics, and therapeutic effects of CNS drugs. In this review the term “Mastermind approach” is introduced, for strategic and systematic CNS drug research using advanced preclinical experimental designs and mathematical modeling. In this way, knowledge can be obtained about the contributions and variability of individual processes on the causal path between drug dosing and CNS effect in animals that can be translated to the human situation. On the basis of a few advanced preclinical microdialysis based investigations it will be shown that the “Mastermind approach” has a high potential for the prediction of human CNS drug effects.
96 citations
Cites background from "Preclinical prediction of human bra..."
...In humans, at best, cerebrospinal fluid (CSF) concentrations can be obtained as a surrogate for brain target site concentrations [13-16], but the value of this surrogate is questionable [17]....
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...As a surrogate for the concentrations of unbound drug at target sites, CSF concentrations are often used and considered appropriate [16,83], however, a generally applicable relationship between CSF and brain ECF concentrations is questionable [5,15,17,134]....
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...This can be done, for example, by changing plasma protein binding [123,124], inhibition of a particular efflux transporter [125], blocking particular receptors [126,127], or by induction of a pathological state [113,128] and enabling us to learn about the contribution of individual processes in CNS target site kinetics [17] and dynamics [129,130]....
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References
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TL;DR: Specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood–brain barrier function are explored to lead to the development of new protective and restorative therapies.
Abstract: The blood-brain barrier, which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. At present, there is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization. Here, we explore specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood-brain barrier function. An understanding of how these interactions are disturbed in pathological conditions could lead to the development of new protective and restorative therapies.
4,578 citations
TL;DR: The results suggest that the protein has a role in the normal secretion of metabolites and certain anti-cancer drugs into bile, urine, and directly into the lumen of the gastrointestinal tract.
Abstract: Monoclonal antibody MRK16 was used to determine the location of P-glycoprotein, the product of the multidrug-resistance gene (MDR1), in normal human tissues. The protein was found to be concentrated in a small number of specific sites. Most tissues examined revealed very little P-glycoprotein. However, certain cell types in liver, pancreas, kidney, colon, and jejunum showed specific localization of P-glycoprotein. In liver, P-glycoprotein was found exclusively on the biliary canalicular front of hepatocytes and on the apical surface of epithelial cells in small biliary ductules. In pancreas, P-glycoprotein was found on the apical surface of the epithelial cells of small ductules but not larger pancreatic ducts. In kidney, P-glycoprotein was found concentrated on the apical surface of epithelial cells of the proximal tubules. Colon and jejunum both showed high levels of P-glycoprotein on the apical surfaces of superficial columnar epithelial cells. Adrenal gland showed high levels of P-glycoprotein diffusely distributed on the surface of cells in both the cortex and medulla. These results suggest that the protein has a role in the normal secretion of metabolites and certain anti-cancer drugs into bile, urine, and directly into the lumen of the gastrointestinal tract.
2,757 citations
TL;DR: A significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function is observed and this polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of M DR-1.
Abstract: To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.
2,452 citations
TL;DR: The findings explain some of the side effects in patients treated with a combination of carcinostatics and P-glycoprotein inhibitors and indicate that these inhibitors might be useful in selectively enhancing the access of a range of drugs to the brain.
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TL;DR: A model of drug pharmacodynamic response that when integrated with a pharmacokinetic model allows characterization of the temporal aspects of pharmacodynamics as well as the time‐independent sensitivity component and can accommodate extremes of effect is proposed.
Abstract: We propose a model of drug pharmacodynamic response that when integrated with a pharmacokinetic model allows characterization of the temporal aspects of pharmacodynamics as well as the time-independent sensitivity component. The total model can accommodate extremes of effect. It allows fitting of simultaneous plasma concentration (Cp) and effect data from the initial distribution phase of drug administration, or from any non-equilibrium phase. The model postulates a hypothetical effect compartment, the dynamics of which are adjusted to reflect the temporal dynamics of drug effect. The effect compartment is modeled as an additional compartment linked to the plasma compartment by a first-order process, but whose exponential does not enter into the pharmacokinetic solution for the mass of drug in the body. The hypothetical amount of drug in the effect compartment is then related to the observed effect by the Hill equation, a nonlinear sigmoid form. Nonlinear least-squares data fitting is used for parameter estimation. The model is demonstrated on two different sets of Cp and effect data for the drug d-tubocurarine (dTC). In 7 normal subjects, the (mean +/- SD) rate constant for equilibration of dTC effect (paralysis) and Cp is 0.13 +/- 0.04 min-1 and the (mean +/- SD) steady-state Cp required to produce 50% paralysis is 0.37 +/- 0.05 microgram/ml.
1,055 citations