PKPD aspects of brain drug delivery in a translational perspective

Abstract

The development and optimization of CNS drug is hampered by the inaccessibility of the human brain and the difficulty to quantify human CNS drug effects. The use of serial CSF sampling in animals and mathematical modeling of plasma pharmacokinetics, in conjunction with CNS effects, provided only useful information for drugs that distribute to the brain target site by simple diffusion and having direct and reversible CNS effects. Active transport processes across blood– brain barriers and brain cell membranes may be applicable for many drugs and should be taken into account. Also, context dependencies of the rates and extents of all transport processes should be included. This indicates the need for crosscompare designed preclinical experimental approaches and mathematical modeling to provide information on contributions of the (main) individual processes, in terms of rate and extent, as well as their interplay, to be able to predict human CNS drug effects.