Small-Molecule Compounds Exhibiting Target-Mediated Drug Disposition (TMDD): A Minireview

Abstract

Nonlinearities are commonplace in pharmacokinetics, and 1 special source is the saturable binding of the drug to a high-affinity, low-capacity target, a phenomenon known as target-mediated drug disposition (TMDD). Compared with large-molecule compounds undergoing TMDD, which has been well recognized due to its high prevalence, TMDD in small-molecule compounds is more counterintuitive and has not been well appreciated. With more and more potent small-molecule drugs acting on highly specific targets being developed as well as increasingly sensitive analytical techniques becoming available, many small-molecule compounds have recently been reported to have nonlinear pharmacokinetics imparted by TMDD. To expand our current knowledge of TMDD in small-molecule compounds and increase the awareness of this clinically important phenomenon, this minireview provides an overview of the small-molecule compounds that demonstrate nonlinear pharmacokinetics imparted by TMDD. The present review also summarizes the general features of TMDD in small-molecule compounds and highlights the differences between TMDD in small-molecule compounds and large-molecule compounds.

Simultaneous Target-Mediated Drug Disposition Model for Two Small-Molecule Compounds Competing for Their Pharmacological Target: Soluble Epoxide Hydrolase

“…Although the concept of TMDD was raised by Levy 25 years ago based on the unusual nonlinear pharmacokinetics of a number of small-molecule drugs, TMDD only became a widelyknown concept with the proliferation of large-molecule biologics because numerous protein drugs demonstrate nonlinear pharmacokinetics imparted by TMDD due to their specific binding to their pharmacological targets (Levy, 1994;Dua et al, 2015). Due to the relatively low prevalence of TMDD in small-molecule drugs, it has been an overlooked area (An, 2017;van Waterschoot et al, 2018), misunderstanding has evolved that "TMDD cannot occur in small-molecule compounds". This is a clear misconception and our study has provided direct evidence that TMDD can occur in small-molecule compounds.…”

General Pharmacokinetic Features of Small‐Molecule Compounds Exhibiting Target‐Mediated Drug Disposition (TMDD): A Simulation‐Based Study

“…Among all small-molecule drugs that were reported to exhibit TMDD, only vildagliptin is metabolized by its pharmacologic target, DPP-4. 23 Considering the low frequency of drug-target complex degradation in small-molecule compounds, in our model there is no additional elimination process for the drug-target complex. Furthermore, we assume that the drug has no nonspecific binding to plasma proteins, such as albumin and alpha-acid glycoprotein, and there is no rate-limiting factor in the distribution of drug between plasma and tissue.…”

“…[16][17][18][19][20][21][22] We have provided an overview of TMDD in smallmolecule compounds in a recent mini-review article and listed the individual small-molecule drugs that have been reported to exhibit TMDD. 23 TMDD in smallmolecule compounds could be caused by saturable binding to targets located in tissues and/or plasma. Depending on the location of the binding targets, the behavior of nonlinear pharmacokinetics imparted by TMDD could be very different among various small-molecule compounds.…”

Target-mediated drug disposition with drug–drug interaction, Part I: single drug case in alternative formulations

“…The TMDD approach for a single drug finds broad application in PK modeling, see [4, 5] for a list of compounds. TMDD behavior is used in several scenarios, such as binding of one drug to two targets [6], for antibody-drug conjugates [7], or receptor mediated endocytosis [8], just to name a few.…”