Prediction of CNS target site pharmacokinetics in humans
Predicting target site concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system
Brain target site concentrations cannot easily be predicted, as drug distribution into and within the brain is influenced by many factors, including blood-brain barrier transport. Moreover, obtaining pharmacokinetic data from the human brain is highly limited.
Our goal is to develop a physiologically-based brain pharmacokinetic model that can be translated to human and to several pathophysiological conditions using in vitro or in silico drug property data. To achieve this, for a series of compounds with distinctive physical-chemical properties, we have first collected extensive unbound rat pharmacokinetic data from plasma and different physiological brain compartments. These include brain extracellular fluid and different sites of cerebrospinal fluid. By combining this diversity in pharmacokinetic data with the distinctive physicochemical properties, we will validate the model while the replacement of rat to human physiological parameters will allow for the translation to human. Ultimately, the impact of disease conditions on drug distribution into and within the brain will be addressed.