Concept of Pharmacologic Target‐Mediated Drug Disposition in Large‐Molecule and Small‐Molecule Compounds

Abstract

Target‐mediated drug disposition (TMDD) is a term to describe a nonlinear pharmacokinetic (PK) phenomenon that is caused by high‐affinity binding of a compound to its pharmacologic targets. As the interaction between a drug and its pharmacologic target belongs to the process of pharmacodynamics (PD), TMDD can be viewed as a consequence of “PD affecting PK.” Although there are numerous TMDD‐related articles in the literature, most of them focus on characterizing TMDD using various mathematical models, which may not be suitable for those readers who have little interest in mathematical modeling and only want to have an understanding of the basic concept. The goal of this review is to serve as a “primer” on TMDD. This review explains (1) how TMDD happens; (2) why large‐molecule and small‐molecule compounds exhibiting TMDD demonstrate substantially different nonlinear PK behaviors; (3) what nonlinear PK profiles look like in large‐molecule and small‐molecule compounds exhibiting TMDD, using pegfilgrastim, erythropoietin, ABT‐384, and linagliptin as case examples; and (4) how to identify whether the nonlinear PK of a compound is because of TMDD.

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

“…3) Interestingly, we observed TCPU plasma concentration peaks right after time 0 (TPPU added) in one group of re-used mice that was administrated TCPU 2 weeks previously, which accidently supported the hypothesis that TCPU could also be displaced by TPPU reversely. Our findings strongly suggested that the pharmacokinetics of TPPU and TCPU were influenced by the specific binding to their pharmacologic target sEH, a phenomenon known as target-mediated drug disposition phenomenon (TMDD) (Levy, 1994;An, 2020).…”

“…This is a clear misconception and our study has provided direct evidence that TMDD can occur in small-molecule compounds. To verify the occurrence of pharmacological TMDD, a number of mechanism experiments have been recommended, including pharmacokinetic experiment using pharmacological target knock-out animals as well as in vivo displacement experiment with co-administration of pharmacological target binding displacer (Veng-Pedersen et al, 1997;Retlich et al, 2009;An, 2017;An, 2020). So far only a few groups have done such mechanism experiments to verify TMDD in large-molecule and small-molecule compounds but none of them have done both experiments within the same study (Veng-Pedersen et al, 1997;Retlich et al, 2009) Both recommended experiments have been performed in our study, which represent an advantage of our work.…”

A target‐mediated drug disposition population pharmacokinetic model of GC1118, a novel anti‐EGFR antibody, in patients with solid tumors

“…However, in patients who received GC1118, it is likely that the total amount of EGFR (TR P ) remains constant because antibody-drug complex do not synthesize its target or EGFR in our case. 26,27 In this case, the degradation rate of EGFR becomes equal to that of the GC1118-EGFR complex. 26 Of course, this assumption may not hold completely true if the amount of EGFR is affected by GC1118.…”

Target‐Mediated Drug Disposition—A Class Effect of Soluble Epoxide Hydrolase Inhibitors

“…For those drugs with capacity limited metabolism, the typical behavior is that the nonlinear pharmacokinetics occur at high doses. However, for small‐molecule compounds undergoing pharmacological target‐mediated nonlinear PK, their nonlinearity occurs at low doses 2,3 . Because of this counterintuitive behavior, the concept of TMDD in small‐molecule compounds has not been widely recognized/appreciated.…”

“…However, the phenomenon of TMDD is not unique to large‐molecule compounds. Several lines of evidence indicate that TMDD can also happen in small‐molecule compounds (eg, warfarin, imirestat, bosentan, linagliptin, selegiline) 2–4 . Moreover, TMDD in small‐molecule compounds appears to be a class effect.…”