Mechanism-based PKPD modelling of CNS-active drugs
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1
Leiden University, LACDR/Pharmacology, Gorlaeus Laboratories, Netherlands
Our ultimate goal is to develop mechanism-based pharmacokinetic (PK)-pharmacodynamic (PD) models to characterize and to predict CNS drug responses in both physiologic and pathologic conditions. To this end, it is essential to have information on the target site (biophase) pharmacokinetics, because it may significantly differ from plasma pharmacokinetics. It is anticipated that the biophase kinetics of CNS drugs in many cases is strongly influenced by transport across the blood-brain barrier (BBB). In vivo microdialysis enables the determination of free-drug concentrations as a function of time in extracellular fluid of the brain, thereby providing important data to determine BBB transport characteristics of drugs. This is important for delineating the mechanisms that govern biophase pharmacokinetics when combined with CNS effect measurements, and therefore provides an indispensable tool in mechanism-based PKPD modeling of CNS drugs.
The biophase kinetics of a CNS drug is an important determinant of the time course and intensity of its CNS effects. Biophase pharmacokinetics can be estimated by PKPD modeling by using a hypothetical effect compartment. This hypothetical effect compartment is linked to the plasma compartment by a rate constant for influx and a rate constant for drug efflux such that there is no time delay between the biophase pharmacokinetics in the effect compartment and the time course of the effect. These data on biophase pharmacokinetics can be related to the effect, whereby it is possible to gain information on the true ability of a drug to activate the receptor. This is typically done using the biophase pharmacokinetics of a number of drugs within a same class, in combination with the receptor theory (operational model of agonism).
However, the use of the effect compartment model does not provide insight into mechanisms that govern biophase pharmacokinetics which is needed for more generally applicable PKPD models. Apart from plasma pharmacokinetics, mechanisms that govern CNS biophase kinetics include: the rate and extent of blood-brain barrier (BBB) transport; the kinetics of processes of distribution and elimination within the brain; target interaction, and signal transduction (fig 1). All the mechanisms may vary in their contribution to the dose-effect relationship and therefore need to be taken into consideration1.
As BBB transport and brain distribution often do not occur instantaneously and to a full extent, this may contribute to a delay of the pharmacologic effect versus time profile relative to the plasma profile. In order to develop more generally applicable models with more power for extrapolation to other conditions, it is of importance to explicitly investigate BBB transport.
BBB transport is related to BBB functionality and occurs by passive diffusion, as well as by active transport. Active transport occurs by many membrane transporters such as the Pglycoprotein (Pgp) and the multidrug resistance-associated proteins (MRPs). BBB functionality is dynamically controlled by blood components and the surrounding brain cells by direct contact or indirectly by their extracellular products. Thus, BBB functionality may vary among different physiologic, pathologic, and chronic drug treatment conditions. It is anticipated that such variations in BBB functionality will ultimately affect the biophase kinetics of CNS drugs and therewith the CNS effect-time profile of the drug.
In vivo microdialysis is a technique that enables the determination of the free drug in plasma and its concentrations in extracellular fluid (ECF) the brain as a function of time. Herewith, it provides important information for the determination of BBB transport and brain distribution. A prerequisite for this application is that BBB transport characteristics will not be significantly influenced by microdialysis probe implantation and presence in the brain. This was an initial concern. But based on a series of studies performed to validate the usefulness of intracerebral microdialysis in measurements of passive, as well as active, BBB transport, this prerequisite appears to hold, provided that this technique is used under well-controlled surgical and experimental conditions.
In this presentation the main principles of mechanism-based PKPD modeling of CNS active drugs will be presented, including arguments for the need to include biophase kinetics, followed by the description of factors that govern biophase kinetics of CNS drugs. Then, two examples on studies in rats that include investigations on the impact of BBB transport will be discussed. The first example is on the EEG effects of opioids2, while the second one deals with BBB transport of L-DOPA and its brain conversion to HVA and DOPAC in Parkinson’s diseased brain3.
Acknowledgments
We are grateful to GlaxoSmithKline and Eli Lilly for their collaboration and financing of the studies on the opioids and Parkinson’s disease, respectively.
References
1. Danhof M, De Lange EC, Della Pasqua OE, Ploeger BA, Voskuyl RA. Mechanismâ€Based Pharmacokineticâ€Pharmacodynamic Modeling in Translational Drug Research. Trends Pharmacol Sci, vol. 29, no. 4, pp. 186â€91.
2. Groenendaal D, Freijer J, Rosier A, de Mik D, Nicholls G, Hersey A, Ayrton A, Danhof M and De Lange EC. Pharmacokineticâ€Pharmacodynamic Modeling of the EEG effects of Opioids: Role of Complex Biophase Distribution Kinetics. Eur J Pharm Sci, 34; 149–163, 2008.
3. Ravenstijn PG, Merlini M, Hameetman M, Murray TK, Ward MA, Lewis H, Ball G, Mottart C, de Ville de Goyet C, Lemarchand T, van Belle K, O'Neill MJ, Danhof M, De Lange EC. The Exploration of Rotenone as a Toxin for Inducing Parkinson's Disease in Rats, for Application in BBB Transport and PKâ€PD Experiments. J Pharmacol Toxicol Meth, Vol 57/2 pp 114â€130, 2007.
Conference:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU, Brussels, Belgium, 11 Feb - 12 Feb, 2010.
Presentation Type:
Oral Presentation
Topic:
Presentations
Citation:
De Lange
EC
(2010). Mechanism-based PKPD modelling of CNS-active drugs.
Front. Pharmacol.
Conference Abstract:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU.
doi: 10.3389/conf.fphar.2010.02.00026
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Received:
11 Mar 2010;
Published Online:
11 Mar 2010.
*
Correspondence:
Elizabeth C De Lange, Leiden University, LACDR/Pharmacology, Gorlaeus Laboratories, Leiden, Netherlands, l.lange@lacdr.leidenuniv.nl