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PKPD Aspects of Brain Drug Delivery in a Translational Perspective

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Drug Delivery to the Brain

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 10))

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 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.

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Abbreviations

AR:

Agonist 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

E0:

Effect in the absence of the agonist

EC50 :

Concentration of agonist at half-maximal effect

ECF:

Extracellular fluid

Em:

Maximal effect in the biological system

Emax:

Maximal effect of the agonist

KA:

Agonist-receptor binding dissociation equilibrium constant

Ke:

Density of agonist receptor complex that elicits the half maximal effect

K1e:

First-order rate constant for influx K1e

Keo:

Rate constant for drug efflux from the hypothetical effect compartment

P-gp:

P-glycoprotein

PD:

Pharmacodynamics

PK:

Pharmacokinetics

PKPD:

Pharmacokinetic-pharmacodynamic

RT:

Total receptor density

τ :

Transducer constant (efficacy parameter)

Ve,app:

Apparent volume of distribution in the brain

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  1. Target Site Equilibration Group, Division of Pharmacology, Leiden Academic Center of Drug Research, Leiden, The Netherlands

    Elizabeth C. M. de Lange

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  1. Pharmaceutical Biosciences, Uppsala University Pharmacokinetics and Drug Therapy, Uppsala, Sweden

    Margareta Hammarlund-Udenaes

  2. LACDR/Pharmacology, Leiden University, Leiden, The Netherlands

    Elizabeth C.M. de Lange

  3. Pharmaceutical Sciences Division, University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin, USA

    Robert G. Thorne

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de Lange, E.C.M. (2014). PKPD Aspects of Brain Drug Delivery in a Translational Perspective. In: Hammarlund-Udenaes, M., de Lange, E., Thorne, R. (eds) Drug Delivery to the Brain. AAPS Advances in the Pharmaceutical Sciences Series, vol 10. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9105-7_9

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