Preclinical Prediction of Human Brain Target Site Concentrations: Considerations in Extrapolating to the Clinical Setting

The development of drugs for central nervous system (CNS) disorders has encountered high failure rates. In part, this has been due to the sole focus on blood-brain barrier permeability of drugs, without taking into account all other processes that determine drug concentrations at the brain target site. This review deals with an overview of the processes that determine the drug distribution into and within the CNS, followed by a description of in vivo techniques that can be used to provide information on CNS drug distribution. A plea follows for the need for more mechanistic understanding of the mechanisms involved in brain target site distribution, and the condition-dependent contributions of these mechanisms to ultimate drug effect. As future direction, such can be achieved by performing integrative cross-compare designed studies, in which mechanisms are systematically influenced (e.g., inhibition of an efflux transporter or induction of pathological state). With the use of advanced mathematical modeling procedures, we may dissect contributions of individual mechanisms in animals as links to the human situation. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3577–3593, 2011