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

Abstract

Although target-mediated drug disposition (TMDD) can occur in both large-and small-molecule compounds, TMDD in small-molecule compounds has received much less attention due to its lower prevalence. To facilitate the identification of nonlinear pharmacokinetics of small-molecule compounds caused by TMDD, a comprehensive simulation was conducted in the current study to provide the general pharmacokinetic features of small-molecule compounds exhibiting TMDD. Various conditions, including single escalating intravenous bolus doses, multiple escalating intravenous bolus doses, and intravenous infusion, were simulated for small-molecule compounds with saturable binding to (1) targets located in tissues and (2) targets located in plasma. Sobol global sensitivity analysis was performed to evaluate the impact of key parameters (R max , k on and k off ) in a small-molecule TMDD model on the apparent volume of distribution and apparent clearance. Our simulation data indicated that small-molecule compounds with saturable binding to targets in plasma demonstrate distinctly different TMDD behavior compared with those with binding to targets in tissue. Sobol global sensitivity analysis results showed that, in general, k off is much more influential than k on and R max on apparent clearance and apparent volume of distribution. The TMDD features predicted in various situations in the current work could serve as a valuable reference to help quickly recognize TMDD when it does happen in a small-molecule compound. The TMDD principals summarized based on our simulation could be used to aid pharmacokinetic data interpretation, dose regimen optimization, and clinical trial design of small-molecule drugs exhibiting TMDD.

Pharmacokinetic Modeling of Warfarin І – Model-Based Analysis of Warfarin Enantiomers with a Target Mediated Drug Disposition Model Reveals CYP2C9 Genotype-Dependent Drug-Drug Interactions of S-Warfarin

“…In addition, several studies published recently readdressed the importance of the application of the TMDD models in small molecule drugs as well (Yamazaki et al, 2013;An et al, 2015;An, 2017). The PK models used for fitting both S-and R-warfarin PK profiles are adapted from the TMDD model proposed for warfarin by Levy et al (Levy et al, 2003;Bach et al, 2019) (Figure 2). The model is described by equations (1-6) as shown below.…”

A Target‐Mediated Drug Disposition Model to Explain Nonlinear Pharmacokinetics of the 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitor SPI‐62 in Healthy Adults

“…Both large-molecule and small-molecule compounds can have TMDD, but they demonstrate substantially different nonlinear pharmacokinetic behaviors because the former is mainly driven by target-mediated elimination, while the latter is mainly affected by target-mediated distribution 14 . For small-molecule compounds exhibiting TMDD with target located in tissues, the key features include 1) nonlinear pharmacokinetics at low doses and linear pharmacokinetics at high doses following single doses; 2) very large apparent volume of distribution at low doses, which decreases quickly as dose increases and reaches a limit at high doses; 3) nonlinear PK following the first dose, but linear PK after repeated doses; 4) unusually high accumulation of drug following repeated low doses, which cannot be explained by the compound's known half-life [14][15][16] . Using these general features as the "diagnostic tool", it is self-evident that the "symptoms" of the nonlinear pharmacokinetics observed in SPI-62 are fully in line with the TMDD principles for small-molecule compounds with targets located in tissues.…”

“…Structural model. As the substantial nonlinear PK behaviors of SPI-62 in humans were fully in line with the known TMDD principles for small-molecule compounds, 15,16 models with TMDD components were tested directly. Several TMDD models were explored during the model-building process, including different compartment models (eg, 1-compartment vs 2compartment) as well as different number of transit compartments (0, 1, 2, 3, and 4 transits) during the absorption process.…”

Impact of target‐mediated drug disposition on hetrombopag pharmacokinetics and pharmacodynamics in Chinese healthy subjects and patients with chronic idiopathic thrombocytopenic purpura

“…[30][31][32][33] Yet, in more and more cases, TMDD models have been adopted for small-molecule drugs as a more mechanistic-based strategy, which provides better support for dose regimen selection. [34][35][36] Initially, the model was tested in the binding and metabolism of hetrombopag in both plasma and tissues, but an overparameterization phenomenon was observed. Thus, the targetmediated drug disposition in the peripheral compartment was removed.…”

“…The TMDD model is generally applied to large‐molecule drugs 30–33 . Yet, in more and more cases, TMDD models have been adopted for small‐molecule drugs as a more mechanistic‐based strategy, which provides better support for dose regimen selection 34–36 . Initially, the model was tested in the binding and metabolism of hetrombopag in both plasma and tissues, but an overparameterization phenomenon was observed.…”