Prediction of Brain Target Site Concentrations on the Basis of CSF Pk : Impact of mechanisms of blood-to-brain transport and within brain distribution

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. Besides plasma pharmacokinetics (PK), plasma protein binding, and passive and active transport across the blood-brain barriers (the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB)), processes within the brain can also influence brain target site PK, including bulk flow, diffusion, and extra-intracellular exchange. Each of the different processes that determine drug concentrations at the relevant CNS target has its particular influence on the overall rate and extent, and thereby plays a more or less important role in having the drug in the right place, at the right time, and at the right concentration. This book presents the mechanistic investigations on the contribution of the different processes that govern the brain target site exposure using a preclinical brain distribution model and a systems-based pharmacokinetic (SBPK) modeling approach.