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.