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 bloodbrain 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. Abbreviations ARAgonist receptor complex density BBB Blood-brain barrier BCSFB Blood-cerebrospinal fluid barrier Ce Concentration of the drug in the effect compartment CNS Central nervous system CSF Cerebrospinal fluid E Effect

Design and Measurement of Drug Tissue Concentration Asymmetry and Tissue Exposure-Effect (Tissue PK-PD) Evaluation

“…Therefore, when compared to other areas, neuroscience translational PK-PD modeling is used less frequently in the pharmaceutical industry . In addition, the difficulties to quantify and evaluate human CNS drug efficacy and the inaccessibility of the human brain are significant barriers to the development of CNS drugs . For drugs that have a direct, reversible effect and that penetrate the brain by passive diffusion, the use of mathematical model correlating plasma and cerebrospinal fluid concentrations can provide valuable information.…”

“…73 In addition, the difficulties to quantify and evaluate human CNS drug efficacy and the inaccessibility of the human brain are significant barriers to the development of CNS drugs. 74 For drugs that have a direct, reversible effect and that penetrate the brain by passive diffusion, the use of mathematical model correlating plasma and cerebrospinal fluid concentrations can provide valuable information. However, when active transportation through the blood-brain barrier (BBB) and cell membranes are part of the mechanism of how the drug reaches the brain, those processes need to be taken into consideration.…”

Translational aspects of blood–brain barrier transport and central nervous system effects of drugs: From discovery to patients

“…The question remains: to which one of these concentrations is the time course of CNS drug effects most closely related? To that end, the link between drug concentrations and effect measures should be investigated …”