caa a22 4500 605533741 CHVBK 20210128100839.0 cr unu---uuuuu 210128e20150201xx s 000 0 eng 10.1007/s10928-014-9401-1 doi (NATIONALLICENCE)springer-10.1007/s10928-014-9401-1 Simulations of site-specific target-mediated pharmacokinetic models for guiding the development of bispecific antibodies [Elektronische Daten] [Vaishali Chudasama, Anup Zutshi, Pratap Singh, Anson Abraham, Donald Mager, John Harrold] 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. Springer Science+Business Media New York, 2015 Bispecific antibodies nationallicence Ulcerative colitis nationallicence Asthma nationallicence Systemic lupus erythematous nationallicence Pharmacokinetics nationallicence Pharmacodynamics nationallicence Chudasama Vaishali Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA aut Zutshi Anup Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA aut Singh Pratap Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA aut Abraham Anson Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA aut Mager Donald Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA aut Harrold John Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/1(2015-02-01), 1-18 1567-567X 42:1<1 2015 42 10928 https://doi.org/10.1007/s10928-014-9401-1 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-014-9401-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Chudasama Vaishali Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Zutshi Anup Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA aut NATIONALLICENCE 700 1- Singh Pratap Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA aut NATIONALLICENCE 700 1- Abraham Anson Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA aut NATIONALLICENCE 700 1- Mager Donald Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Harrold John Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/1(2015-02-01), 1-18 1567-567X 42:1<1 2015 42 10928