Dissertation

Prediction of brain target site concentrations on the basis of CSF PK: impact of mechanisms of blood-to-brain transport and within brain distribution

Promotor: Prof.dr. M. Danhof, Co-promotor: E.C.M. de Lange

Author: J. Westerhout
Date: 06 March 2014
Links: Thesis in Leiden Repository

In the development of drugs for the treatment of central nervous system (CNS) disorders, the prediction of human CNS drug action is a big challenge. Direct measurement of brain extracellular fluid (brainECF) concentrations is highly restricted in human. Therefore, unbound drug concentrations in human cerebrospinal fluid (CSF) are used as a surrogate for human brainECF concentrations. Due to qualitative and quantitative differences in processes that govern the pharmacokinetics (PK) of drugs in the brain, a generally applicable relationship between CSF concentrations and brainECF concentrations does not exist. The aim of the research presented in this thesis was to develop a preclinical brain distribution model, allowing the prediction of human brain target site concentrations on the basis of preclinical data. In order to be able to build a brain distribution model understanding of time-dependent (also non-steady state) kinetics of the unbound drug in brainECF and CSF is essential. To that end, systematic studies on the inter-relationship of plasma PK, blood-brain barrier (BBB) transport, blood-CSF barrier (BCSFB) transport and intra-brain distribution were performed in the rat by implantation of microdialysis probes at multiple brain sites in individual animals