Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics
Introduction
Delivery to the central nervous system (CNS) remains an obstacle in the development of new centrally acting drugs. The main challenge is the design of drug candidate molecules that can effectively traverse the blood–brain and blood–cerebrospinal fluid barriers (i.e., BBB and BCSFB). For drug candidates intended for peripheral action, at times an opposite challenge is encountered, that of minimizing their distribution to the CNS and occurrence of centrally mediated side effects or adverse reactions.
During the past 10 years, a number of in vitro cell culture models have been developed for the purpose of predicting the passage of drug candidates across the BBB and the BCSFB [1]. These in vitro systems are now widely used during drug discovery to screen and rank-order compounds according to their likelihood of CNS penetration. However, given the multiple routes of drug entry into and exit from the brain and the complexity in drug distribution among the various brain structures and fluid compartments, it is unlikely that in vitro BBB models alone can provide accurate, quantitative predictions of in vivo CNS availability. As a result, the ability of promising drug candidates to enter the CNS is often confirmed by in vivo studies during the later stages of the candidate selection and development process. This then raises the question of what is the most cost-effective in vivo method to assess the CNS availability of candidate compounds.
In vivo CNS availability may be determined by sampling brain tissue, cerebrospinal fluid (CSF), or brain extracellular or interstitial fluid (ISF) concentrations at various times after systemic administration of a compound. Brain tissue sampling is costly in terms of animal use, especially if multiple sample times are desired, and the need to develop drug and metabolite assays in brain tissue. More critical is the issue of what is the relevant site to sample in the brain. Concentration measurement in a homogenate of the whole brain may not represent the concentration of a candidate compound and its metabolites at their site(s) of action. Dissection of the brain into regions or isolation of a discrete structure can be considered. Unfortunately, more often than not the particular structure(s) or region(s) involved in the pharmacology of new drug candidates are not fully understood or known. A further problem is the confounding presence of non-specific binding or sequestration of a candidate compound in the brain tissue, which may obscure the true nature of the localization of the compound at the site(s) of action. These complications have led a number of investigators to suggest the use of drug concentration in CSF and, more recently, brain ISF as a surrogate marker for CNS availability. Of the two sampling methods, CSF is clearly the more practical approach in terms of effort, cost and throughput. Serial CSF sampling can easily be performed through catheters inserted into the cisterna magna or lumber intrathecal space, which affords detailed information on drug concentration time course in the CNS. In large animals, such as the dog or non-human primates, repeated studies in the same chronically catheterized animal allow crossover studies when comparing a series of candidate compounds. It is doubtful that ISF sampling by microdialysis will ever match the practical advantage of CSF sampling in early drug discovery and development.
Sampling of CSF and, more recently, ISF have been used to characterize the pharmacokinetic–pharmacodynamic (PK–PD) correlation of CNS-active drugs in animals. This is particularly applicable in elucidating the lag in the time course of a central pharmacologic effect relative to that of drug concentration in the circulation following systemic drug administration (i.e., as revealed by a counterclockwise hysteresis plot of effect versus blood or plasma concentration) [2]. Through simultaneous sampling of CSF and ISF, it is possible to assess whether the delay in effect–concentration equilibration is due to a slow exchange of the drug across the BBB or BCSFB, or to a delay in the expression of the pharmacologic end-point (i.e., whether it is a pharmacokinetic lag or a reflection of intrinsic pharmacodynamics).
The purpose of the present review is to examine the applicability and limitation of CSF sampling as a tool for investigating CNS pharmacokinetics in the context of CNS drug delivery and that of PK–PD correlation. We will examine the available evidence that support the use of CSF concentration as a marker of drug availability to the effect site or biophase. The crucial argument for CSF as an appropriate CNS sampling site has relied on the assumption that drug concentration in the CSF is in equilibrium with the biophase, regardless of whether it exists at a single or multiple sites (i.e., the brain exhibits kinetic characteristics of a homogeneous compartment at steady-state). In other words, CSF concentration represents the ‘unbound’ or ‘free’ concentration in the brain when steady-state equilibration of freely diffusible drug concentration is achieved throughout the brain; this is an extension of the traditional ‘free drug hypothesis’ in pharmacokinetics. Given the heterogeneous and complex structure and physiology of the brain, it is perhaps not surprising that the simplistic assumption of a unifying ‘free concentration’ as reflected in the CSF concentration is not always followed. Accordingly, we will present literature examples that point to situations when the CSF concentration does and does not reflect the kinetics of the drug access to the biophase within the brain. A key part of our discussion will rely on the recent advances in our understanding of the pharmacokinetic relationship between CSF and the brain ISF. The reader is referred to two earlier reviews by Bonati et al. [3] and de Lange and Danhof [4] on similar topics pertaining to CSF pharmacokinetics and the use of CSF to predict drug concentration at the brain target site(s).
We will begin by reviewing the pertinent aspects of CSF and ISF physiology to provide a conceptual framework for our discussion on the use of CSF sampling in pharmacokinetics.
Section snippets
Physiologic considerations
This section presents a summary of our current understanding of the anatomy and physiology of ISF and CSF. It points to the obvious fact that, together, these two fluid systems act as the circulatory network for the CNS. The discussion will focus on how solutes that enter the brain or are produced within the brain parenchymal cells are conveyed between these two fluid compartments and transported throughout the cerebral and spinal regions. The presentation illustrates the complex and
Pharmacokinetic considerations
The presentation on CSF and ISF physiology in Section 2 illustrates the heterogeneity of the CNS circulatory system. Following systemic administration of a drug, differences in drug concentrations between ISF and CSF, as well as variations between regions or along the flow path appear to be the norm, rather than the exception. With respect to the question of whether CSF concentration can serve as a reference for assessing the extent of drug delivery to the pharmacological targets within the CNS
Plasma–CSF–brain partitioning of drugs
In this final section, we present the results of an analysis of plasma–CSF–brain partitioning data on 104 drugs from 10 therapeutic classes: antiepileptics, drugs for Parkinson's and Alzheimer's diseases, antipsychotics, antidepressants, anesthetics, analgesics (opioids and NSAIDs), antibiotics, antiretrovirals, and anticancer drugs.1
Concluding remarks
Despite the complexity of CSF physiology and pharmacokinetics, CSF penetration studies in animals remain a practical option for the assessment of CNS drug delivery in early preclinical drug development, when throughput and efficiency are the over-riding concerns. CSF concentration is a reasonably good discriminating indicator of drug availability to the CNS for hydrophilic or large molecular weight compounds with poor to moderate permeability. Comparison of observed CSF concentrations for a
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