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

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 end

SUBMITTER: Yuan D 

PROVIDER: S-EPMC6824202 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature