Target-mediated exposure enhancement: a previously unexplored limit of TMDD
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ORIGINAL PAPER
Target-mediated exposure enhancement: a previously unexplored limit of TMDD Patrick M. Glassman1
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Vladimir R. Muzykantov1
Received: 13 December 2019 / Accepted: 28 May 2020 Ó Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Target-mediated drug disposition (TMDD) is often observed for targeted therapeutics, and manifests as decreases in clearance and volume of distribution with increasing dose as a result of saturable, high affinity target binding. In the present work, we demonstrate that classically defined TMDD is just one of the characteristic features of the system. In fact, for molecules with rapid non-specific elimination relative to target-mediated elimination, binding to target may actually lead to improved exposure at sub-saturating doses. This feature, which we refer to as target-mediated exposure enhancement (TMEE), produces the opposite trend to classical TMDD, i.e., with increasing dose levels, clearance and volume of distribution will also increase. The general model of TMDD was able to well-characterize the pharmacokinetics of two molecules that display TMEE, ALX-0081 and linagliptin. Additional fittings using the commonly reported TMDD model approximations revealed that both the quasi-equilibrium and quasi-steady-state approximations were able to well-describe TMEE; however, the Michaelis–Menten approximation was unable to describe this behavior. With the development of next-generation therapeutics with high affinity for target and rapid non-specific elimination, such as antibody fragments and peptides, this previously unexplored limit of TMDD is anticipated to become increasingly relevant for describing pharmacokinetics of investigational therapeutics. Keywords Pharmacokinetics Target-mediated drug disposition Pharmacokinetic modeling Nonlinear pharmacokinetics
Introduction Nonlinear pharmacokinetics (PK) is a common observation for many targeted therapeutics, in particular monoclonal antibodies (mAbs) and their derivatives [1, 2]. This phenomenon, referred to as target-mediated drug disposition (TMDD) was first described by Gerhard Levy in his seminal 1994 publication [3]. By definition, TMDD is a pharmacokinetic (PK) phenomenon wherein specific binding between drug and target has a significant impact on Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10928-020-09693-1) contains supplementary material, which is available to authorized users. & Patrick M. Glassman [email protected] 1
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Bldg 421, 10-178 Translational Research Center, Philadelphia, PA 19104-5158, USA
drug behavior in vivo. TMDD is observed with increasing regularity in drug discovery and development, due to high affinity interactions between drug and receptors, which are often internalizing in nature. In the majority of reported cases, TMDD manifests as non-linear PK, defi
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