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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 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.

SUBMITTER: Yuan D

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

REPOSITORIES: biostudies-literature

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

Yuan Dongfen D Rode Frederik F Cao Yanguang Y

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 20190805

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 ...[more]

PMID: 31394258

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Dataset Information

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

Publications

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

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