Comparisons of basic target-mediated drug disposition (TMDD) and ligand facilitated target removal (LFTR).

In the well-known model for basic Target-Mediated Drug Disposition (TMDD), drug binds to the target and the resulting drug-target complex is removed by a first order process, leading to loss of both drug and target. In the present note we study what happens when, instead, drug is returned to the free drug pool so that it can a new target molecule. What results is a mechanism in which the drug, here referred to as the ligand, facilitates the removal of the target,and then returns to the free ligand pool. Accordingly the process will be referred to as Ligand-Facilitated Target Removal (LFTR). It is shown through simulations and mathematical analysis how the two models differ and how their signature profiles typically appear. We also derive a useful parameter of both models, the in vivo potency EC50 (L50) which contains both ligand-target binding properties (kon,koff), target turnover (kdeg) and ligand-target complex kinetics (ke(RL)). Thus, this parameter contains a conglomerate of properties and is therefore potentially more informative about relevant (clinical) exposure than the binding affinity (Kd) alone. The derived potency parameter EC50 may therefore be used as a more robust ranking parameter among small and large drug molecules in drug discovery. Subsequently the LFTR model is applied to experimentally obtained literature data and the relevant parameters are estimated. Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.

Citation

Lambertus A Peletier, Rasmus Jansson-Löfmark, Johan Gabrielsson. Comparisons of basic target-mediated drug disposition (TMDD) and ligand facilitated target removal (LFTR). European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2021 Jul 01;162:105835

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PMID: 33848634

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