A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies

摘要

Concizumab is a humanized monoclonal antibody in clinical investigation directed against membrane-bound and soluble tissue factor pathway inhibitor (mTFPI and sTFPI) for treatment of hemophilia. Concizumab displays a non-linear pharmacokinetic (PK) profile due to mTFPI-mediated endocytosis and necessitates a high dose and frequent dosing to suppress the abundant sTFPI, a negative regulator of coagulation. Recycling antibodies that can dissociate bound mTFPI/sTFPI in endosomes for degradation and rescue antibody from degradation have a potential in reducing the dose by extending antibody systemic persistence and sTFPI suppression. We developed a systems PK/pharmacodynamics (PD) model with nested endosome compartments to simulate the effect of decreased antibody binding to mTFPI/sTFPI in endosomes on antibody clearance and sTFPI suppression for exploring the potential of anti-TFPI recycling antibodies in reducing the dose. A dynamic model-building strategy was taken. A reduced PK/PD model without the endosome compartments was developed to optimize unknown target turnover parameters using concizumab PK data. The optimized parameters were then employed in the systems PK/PD model for simulations. The obtained systems PK/PD model adequately described the PK of concizumab in rabbits, monkeys, and humans and the PD in humans. The systems PK/PD model predicted that an anti-TFPI recycling antibody with a 100-fold higher mTFPI/sTFPI dissociation constant in endosomes than concizumab can extend sTFPI suppression from 12 days to 1 month. Thus, the systems PK/PD model provides a quantitative platform for guiding the engineering and translational development of anti-TFPI recycling antibodies.