Speaker
Description
Background: MG1113 is a humanized immunoglobulin G4 antibody targeting tissue factor pathway inhibitor (TFPI), currently under clinical development for hemophilia. This study aimed to refine a previously developed TMDD model for MG1113 by incorporating both soluble and membrane-bound TFPI (sTFPI-α and mTFPI) along with a transit compartment. Furthermore, we investigated the impact of baseline target abundance on interindividual pharmacokinetic variability.
Methods: Using the Cluster Gauss-Newton Method (CGNM), the refined TMDD model was fitted to both mean and individual plasma profiles of MG1113 and sTFPI-α in cynomolgus monkeys receiving intravenous and subcutaneous doses. The optimized parameters were allometrically scaled to simulate the concentration-time profiles in rabbits and humans.
Results: The refined TMDD model demonstrated improved performance over the prior model in monkeys and showed good agreement with observed data in rabbits, supporting its interspecies applicability. For humans, simulations predicted that a weekly dose of 3.3 mg/kg MG1113 would maintain sTFPI-α suppression below 25% of baseline. Notably, incorporating individual data allowed the model to effectively capture the distinct pharmacokinetic profiles of each subject.
Conclusions: This model enables quantitative prediction of sTFPI-α suppression based on MG1113 dose and baseline target levels, providing a rationale for precision dosing to overcome interindividual variability in clinical settings.
Acknowledgments
Supported by the Seoul National University Grant (Creative-Pioneering Researchers Program, WL) and by the National Research Foundation of Korea (NRF) Grants from the Korean Government (NRF 2023R1A2C1006820 and RS-2024–00401422, WL).
