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

A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies. Eur J Pharm Sci. 2019 Aug 05;:105032 Authors: Yuan D, Rode F, Cao Y Abstract 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 de...
Source: European Journal of Pharmaceutical Sciences - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharm Sci Source Type: research