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Background and Objective <p>BT-114143 is a novel, small-molecule antifibrinolytic agent that promotes hemostasis by inhibiting the conversion of plasminogen to plasmin. Due to its strong binding to this target, the drug exhibits target-mediated drug disposition (TMDD). This is characterized by nonlinear pharmacokinetics (PK) at low doses that transition to linearity at higher, target-saturating doses. In this study, a population pharmacokinetic-pharmacodynamic (PopPK-PD) model for BT-114143 was developed to guide dose selection for a subsequent multiple ascending dose (MAD) study.</p> Method <p>Using PK and PD data from a single ascending dose (SAD) study of intravenously administered BT-114143, a PopPK-PD model was developed.</p> Results <p>The PopPK-PD analysis established that a TMDD PK model, combined with a sigmoid <i>E</i><sub>max</sub> PD model, adequately characterized the nonlinear PK and antifibrinolytic activity of intravenous BT-114143 in healthy subjects. The model identified the primary drivers of this TMDD behavior as the rapid binding of BT-114143 to plasminogen (association rate constant, <i>K</i>ₒₙ&#xa0;=&#xa0;1.42&#xa0;µM⁻<sup>1</sup>·h⁻<sup>1</sup>), its slow dissociation (dissociation rate constant, <i>K</i><sub>off</sub>&#xa0;=&#xa0;0.0518&#xa0;h⁻<sup>1</sup>), and the estimated total target concentration (<i>R</i>ₜₒₜ&#xa0;=&#xa0;1.6&#xa0;µmol/l). Furthermore, simulations predicted that twice-daily regimens of 2.4, 4.8, and 9.6&#xa0;mg/kg would maintain steady-state trough concentrations (<i>C</i><sub>trough</sub>) above the therapeutic threshold (≥&#xa0;2&#xa0;µmol/l) throughout the dosing period.</p> Conclusion <p>This study reports the first PopPK-PD model for a novel, plasminogen-targeting small-molecule exhibiting TMDD properties. The model was subsequently used to inform and support the design of multiple-dose regimens for future clinical studies in patients.</p>

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Optimization of Dosing Regimens for Plasminogen Activation Inhibitor BT-114143 Using a Small Molecule TMDD Population PK and PD Model in Healthy Subjects

  • 期刊论文

  • 发表日期：

    2026年3月17日

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  • Min Li,
  • Yafen Li,
  • Shaomei Zeng,
  • Yaqi Wang,
  • Yafei Ji,
  • Guo-Ping Yang,
  • Jun Tang

摘要

Background and Objective

BT-114143 is a novel, small-molecule antifibrinolytic agent that promotes hemostasis by inhibiting the conversion of plasminogen to plasmin. Due to its strong binding to this target, the drug exhibits target-mediated drug disposition (TMDD). This is characterized by nonlinear pharmacokinetics (PK) at low doses that transition to linearity at higher, target-saturating doses. In this study, a population pharmacokinetic-pharmacodynamic (PopPK-PD) model for BT-114143 was developed to guide dose selection for a subsequent multiple ascending dose (MAD) study.

Method

Using PK and PD data from a single ascending dose (SAD) study of intravenously administered BT-114143, a PopPK-PD model was developed.

Results

The PopPK-PD analysis established that a TMDD PK model, combined with a sigmoid Emax PD model, adequately characterized the nonlinear PK and antifibrinolytic activity of intravenous BT-114143 in healthy subjects. The model identified the primary drivers of this TMDD behavior as the rapid binding of BT-114143 to plasminogen (association rate constant, Kₒₙ = 1.42 µM⁻1·h⁻1), its slow dissociation (dissociation rate constant, Koff = 0.0518 h⁻1), and the estimated total target concentration (Rₜₒₜ = 1.6 µmol/l). Furthermore, simulations predicted that twice-daily regimens of 2.4, 4.8, and 9.6 mg/kg would maintain steady-state trough concentrations (Ctrough) above the therapeutic threshold (≥ 2 µmol/l) throughout the dosing period.

Conclusion

This study reports the first PopPK-PD model for a novel, plasminogen-targeting small-molecule exhibiting TMDD properties. The model was subsequently used to inform and support the design of multiple-dose regimens for future clinical studies in patients.