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De Witte et al publish in Nature Drug Discovery Reviews

Nature Reviews Drug Discovery volume 18, pages 82–84 (2019). The implications of target saturation for the use of drug–target residence time Wilbert de Witte, Meindert Danhof, Piet van der Graaf, and Elizabeth de Lange

Wilbert de Witte

According to a much quoted publication by Copeland and colleagues from 2006 (https://www.nature.com/articles/nrd2082), binding kinetics determines the residence time of a drug on the target and thus the duration of the drug's action.  However, in the body,  binding kinetics is not the only process that determines the duration of a drug's action. Also, the drugs absorption-, distribution- and elimination kinetics,  target site distribution kinetics, and potential saturation of the targets need to be taken into account. The saturation of drug target binding had been overlooked by Copeland et al.  

De Witte et al.’s analysis indicated that when target saturation in the body is not taken into account, there is no basis for proper understanding of the relationship between drug properties, the in vitro determined residence time of a drug on its target, the duration of action of the drug in the body, in situations other than in the particular studied  subjects or patients. In other words, it cannot be generalized. It is emphasized that for proper prediction of the duration of action of a drug, and based on that, the dosage regime, there is a need for integration of all body processes .


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