PKPD Aspects of Brain Drug Delivery in a Translational Perspective

  • Elizabeth C. M. de Lange
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 10)


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 cross-compare 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.


Intranasal Administration PKPD Model Target Occupancy Prolactin Plasma Concentration Total Brain Concentration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Agonist receptor complex density


Blood–brain barrier


Blood–cerebrospinal fluid barrier


Concentration of the drug in the effect compartment


Central nervous system


Cerebrospinal fluid




Effect in the absence of the agonist


Concentration of agonist at half-maximal effect


Extracellular fluid


Maximal effect in the biological system


Maximal effect of the agonist


Agonist-receptor binding dissociation equilibrium constant


Density of agonist receptor complex that elicits the half maximal effect


First-order rate constant for influx K1e


Rate constant for drug efflux from the hypothetical effect compartment










Total receptor density


Transducer constant (efficacy parameter)


Apparent volume of distribution in the brain


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Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  1. 1.Target Site Equilibration Group, Division of PharmacologyLeiden Academic Center of Drug ResearchLeidenThe Netherlands

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