Abstract
Human cerebrospinal fluid (CSF) sampling is of high value as the only general applicable methodology to obtain information on free drug concentrations in individual human brain. As the ultimate interest is in the free drug concentration at the CNS target site, the question is what CSF concentrations may tell us in that respect. Studies have been performed in rats and other animals for which concentrations in brain extracellular fluid (brain ECF) as a target site for many drugs, have been compared to (cisterna magna) CSF concentrations, at presumed steady state conditions,. The data indicated that CSF drug concentrations provided a rather good indication of, but not a reliable measure for predicting brain ECF concentrations. Furthermore, comparing rat with human CSF concentrations, human CSF concentrations tend to be higher and display much more variability. However, this comparison of CSF concentrations cannot be a direct one, as humans probably had a disease for which CSF was collected in the first place, while the rats were healthy. In order to be able to more accurately predict human brain ECF concentrations, understanding of the complexity of the CNS in terms of intrabrain pharmacokinetic relationships and the influence of CNS disorders on brain pharmacokinetics needs to be increased. This can be achieved by expanding a currently existing preclinically derived physiologically based pharmacokinetic model for brain distribution. This model has been shown to successfully predict data obtained for human lumbar CSF concentrations of acetaminophen which renders trust in the model prediction of human brain ECF concentrations. This model should further evolute by inclusion of influences of drug properties, fluid flows, transporter functionalities and different disease conditions. Finally the model should include measures of target site engagement and CNS effects, to ultimately learn about concentrations that best predict particular target site concentrations, via human CSF concentrations.
Highlights
The treatment of neurological diseases is a huge problem
Reasons for failure of central nervous system (CNS) drug candidates can at least in part be found in inconclusive pharmacokinetic data, regarding blood brain barrier (BBB) transport, inconclusive pharmacodynamic data, and the variability of the data due to the heterogenous nature of CNS pathologies in humans [1]
To answer the first question, it is important to investigate particular the free CNS drug concentrations, These concentrations may serve as the best predictor of drug effects because CNS drug targets such as receptors, enzymes and transporters only interact with the free drug concentration [2,3,4,5,6,7,8,9,10]
Summary
The treatment of neurological diseases is a huge problem. The search for appropriate treatments is under increased pressure as, on one hand, the results of drug candidates in clinical trials are very disappointing, while on the other hand an increase in the incidence of neurological diseases is occurring, probably due to an ageing society and life styles choices. The most straightforward method to obtain information on free drug concentrations in human brain ECF is by cerebrospinal fluid (CSF) sampling. With the later introduction of the microdialysis technique, information on the relationships between CSF concentrations and brain ECF concentrations became available. Such studies were typically performed in rodents because the brain microdialysis technique is invasive, though minimally [12]. Studies will be presented in which CSF and brain ECF concentrations have been assessed and compared, followed by a systematic approach towards that leads to the possibility to use human CSF values to predict target site concentrations of CNS drugs [13]
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