Please cite this article in press as: Smith, D.A. et al. Importance of target-mediated drug disposition for small molecules, Drug Discov Today (2018), https://doi.org/10.1016/j. drudis.2018.06.010 Drug Discovery Today  Volume 00, Number 00  June 2018 REVIEWS Importance of target-mediated drug disposition for small molecules Dennis A. Smith Q1 1 , Robert A.B. van Waterschoot 2 , Neil J. Parrott 2 , Andrés Olivares-Morales 2 , Thierry Lavé 2 and Malcolm Rowland 3 1 Department of Chemistry, University of Cape Town, Cape Town, South Africa 2 Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland 3 Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, UK Target concentration is typically not considered in drug discovery. However, if targets are expressed at relatively high concentrations and compounds have high affinity, such that most of the drug is bound to its target, in vitro screens can give unreliable information on compound affinity. In vivo, a similar situation will generate pharmacokinetic (PK) profiles that deviate greatly from those normally expected, owing to target binding affecting drug distribution and clearance. Such target-mediated drug disposition (TMDD) effects on small molecules have received little attention and might only become apparent during clinical trials, with the potential for data misinterpretation. TMDD also confounds human microdosing approaches by providing therapeutically unrepresentative PK profiles. Being aware of these phenomena will improve the likelihood of successful drug discovery and development. Introduction Not only the selection of an appropriate drug target, but also a thorough understanding of the PK and pharmacodynamics (PD) are crucial to ensure successful drug discovery and development programs [1,2]. Although many drug discovery projects have a solid rationale for the target, there is often little information about its actual concentration, whether in early in vitro screens, the subsequent in vivo animal studies, in healthy subjects, or in patients. This lack of information can affect the program in a variety of ways, from providing unreliable information on com- pound target affinity and potency to having unpredictable and highly variable PK in humans. Q2 The impact of target binding on PK has been discussed periodi- cally [3–6] and the perspective of clinical observations and out- comes was recently reviewed [7–9]. However, relevant concepts have not yet been embedded within the framework of drug dis- covery. Therefore, here we highlight the possible implications of TMDD for reversibly bound small molecules to increase awareness in the drug discovery community that the influence of the target on PK should be considered at the outset. Consideration of drugs acting through irreversible (covalent) binding with targets is be- yond the scope of this review, other than to note that, in contrast to reversibly binding drugs that only affect distribution, irrevers- ibly binding drugs result in an additional pathway for elimination of drug (increase its intrinsic clearance) and target, via the forma- tion of a receptor–metabolite–drug complex, which is ultimately removed via endocytosis. The duration of effect of irreversible binding drugs is largely determined by the rate of disappearance of the receptor–drug complex rather than the free circulating drug, in contrast to the usual rapidly reversibly bound molecules, the duration of action of which relies on the presence of the free drug. Drugs produce their effects in a sequential manner. The first and prerequisite step is one of engagement or binding of the drug with the target, characterised by its kinetics, affinity, and capacity. The higher the affinity, the lower the equilibrium dissociation con- stant of the drug–target complex (Kd). This engagement then produces a cascade of events, some simple, others complex, often called the stimulus, resulting in the response, characterised by potency and efficacy, or maximum response. Potency is often Reviews  POST SCREEN Corresponding author: van Waterschoot, Robert A.B. (robert.van_waterschoot@roche. com) 1359-6446/ã 2018 Published by Elsevier Ltd. https://doi.org/10.1016/j.drudis.2018.06.010 www.drugdiscoverytoday.com 1