Abstract
Despite the enormous research efforts that have been put into the development of central nervous system (CNS) drugs, the success rate in this area is still disappointing. To increase the successful rate in the clinical trials, first the problem of predicting human CNS drug distribution should be solved. As it is the unbound drug that equilibrates over membranes and is able to interact with targets, especially knowledge on unbound extracellular drug concentration-time profiles in different CNS compartments is important. The only technique able to provide such information in vivo is microdialysis. Also, obtaining CNS drug distribution data from human subjects is highly limited, and therefore, we have to rely on preclinical approaches combined with physiologically based pharmacokinetic (PBPK) modeling, taking unbound drug CNS concentrations into account. The next step is then to link local CNS pharmacokinetics to target interaction kinetics and CNS drug effects. In this review, system properties and small-molecule drug properties that together govern CNS drug distribution are summarized. Furthermore, the currently available approaches on prediction of CNS pharmacokinetics are discussed, including in vitro, in vivo, ex vivo, and in silico approaches, with special focus on the powerful combination of in vivo microdialysis and PBPK modeling. Also, sources of variability on drug kinetics in the CNS are discussed. Finally, remaining gaps and challenges are highlighted and future directions are suggested.
Highlights
There is a huge unmet medical need for central nervous system (CNS) disease therapies because of the growing of chronic and complex diseases associated with aging
Knowledge of human CNS drug concentrations forms the basis for understanding exposureresponse relationships; the lack of appropriate consideration of these target concentrations is one of the factors contributing to this high degree of attrition
Pharmacokinetics of drugs in the CNS is governed by a combination of CNS system physiology and drug properties
Summary
There is a huge unmet medical need for central nervous system (CNS) disease therapies because of the growing of chronic and complex diseases associated with aging. A generic multi-compartmental CNS distribution model structure has been proposed, that could successfully describe the pharmacokinetics in plasma and different CNS compartments (brainECF, CSF in the lateral ventricle (CSFLV) and CSF in the cisterna magna (CSFCM)), using microdialysis data for 9 paradigm compounds with substantial differences in physicochemical properties [9] (Table VI, Fig. 3). These compounds are acetaminophen, atenolol, methotrexate, morphine, paliperidone, phenytoin, quinidine, remoxipride, and risperidone. BBB characteristics may change in Alzheimer’s disease, multiple sclerosis, and pharmacoresistant epilepsies [190]
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