Universiteit Leiden

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Research project

Assessment of the impact of in vivo drug-target binding kinetics on local drug concentrations

The IMI project “Kinetics for Drug Discovery” (K4DD) aims to improve the drug discovery process by considering drug-target binding kinetics in the early phase of drug discovery.

Elizabeth (Liesbeth) de Lange

To that end, the K4DD consortium aims to generate understanding of the determinants of binding kinetics, to develop robust assays to measure binding kinetics and to obtain a better understanding of the influence of drug-target binding kinetics on in vivo drug action.

In this project we have been working on the novel approach of combining brain microdialysis and total brain tissue measurements in the rat, in presence of the dopamine D2 receptor tracer non-radiolabeled raclopride, this will allow for label-free measurement of in vivo binding kinetics of D2 antagonists and agonists as paradigm compounds. Pharmacokinetic (PK) data are obtained for plasma, unbound brain extracellular fluid and total tissue (specific D2-receptor binding + non-specific tissue binding) for both the D2 target site striatum and non-D2 reference site cerebellum. This approach shows the value of having two different sources to calculate receptor occupancy in order to discriminate between total D2 receptor occupancy (tracer displacement method) and drug-specific D2 receptor occupancy (modelling-based methods using microdialysis free drug concentration). The receptor occupancy-time profiles are quantitatively elucidated by both the population ("top-down") and physiologically-based ("bottom-up") PK modelling methods. Ultimately, the binding kinetics data for the D2 compounds will be related to translational plasma hormone markers for dopaminergic signalling.


de Witte, W.E.A. et al. (2015) Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients. Expert Opin. Drug Discov. 11, 45–63



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