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Simulations of site-specific target-mediated pharmacokinetic models for guiding the development of bispecific antibodies

  • Vaishali L. Chudasama
  • Anup Zutshi
  • Pratap Singh
  • Anson K. Abraham
  • Donald E. Mager
  • John M. Harrold
Original Paper

Abstract

Bispecific antibodies (BAbs) are novel constructs that are under development and show promise as new therapeutic modalities for cancer and autoimmune disorders. The aim of this study is to develop a semi-mechanistic modeling approach to elucidate the disposition of BAbs in plasma and possible sites of action in humans. Here we present two case studies that showcase the use of modeling to guide BAb development. In case one, a BAb is directed against a soluble and a membrane-bound ligand for treating systemic lupus erythematosus, and in case two, a BAb targets two soluble ligands as a potential treatment for ulcerative colitis and asthma. Model simulations revealed important differences between plasma and tissues, when evaluated for drug disposition and target suppression. Target concentrations at tissue sites and type (soluble vs membrane-bound), tissue-site binding, and binding affinity are all major determinants of BAb disposition and subsequently target suppression. For the presented case studies, higher doses and/or frequent dosing regimens are required to achieve 80 % target suppression in site specific tissue (the more relevant matrix) as compared to plasma. Site-specific target-mediated models may serve to guide the selection of first-in-human doses for new BAbs.

Keywords

Bispecific antibodies Ulcerative colitis Asthma Systemic lupus erythematous Pharmacokinetics Pharmacodynamics 

Notes

Acknowledgments

We wish to thank Drs. Marion Kasaian and Joanne Brodfuehrer for critically reviewing this manuscript.

Conflict of interest

AZ, AKA, PS, are employees of Pfizer, Inc. JMH was an employee of Pfizer while the work was being performed. VLC and DEM declare no conflicts of interest.

Supplementary material

10928_2014_9401_MOESM1_ESM.docx (2.5 mb)
Supplementary material 1 (DOCX 2574 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Vaishali L. Chudasama
    • 1
  • Anup Zutshi
    • 2
  • Pratap Singh
    • 2
  • Anson K. Abraham
    • 2
  • Donald E. Mager
    • 1
  • John M. Harrold
    • 2
  1. 1.Department of Pharmaceutical SciencesUniversity at Buffalo, SUNYBuffaloUSA
  2. 2.Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and MetabolismPfizer Worldwide R&DCambridgeUSA

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