Simulations of site-specific target-mediated pharmacokinetic models for guiding the development of bispecific antibodies
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| 024 | 7 | 0 | |a 10.1007/s10928-014-9401-1 |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s10928-014-9401-1 | ||
| 245 | 0 | 0 | |a Simulations of site-specific target-mediated pharmacokinetic models for guiding the development of bispecific antibodies |h [Elektronische Daten] |c [Vaishali Chudasama, Anup Zutshi, Pratap Singh, Anson Abraham, Donald Mager, John Harrold] |
| 520 | 3 | |a 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. | |
| 540 | |a Springer Science+Business Media New York, 2015 | ||
| 690 | 7 | |a Bispecific antibodies |2 nationallicence | |
| 690 | 7 | |a Ulcerative colitis |2 nationallicence | |
| 690 | 7 | |a Asthma |2 nationallicence | |
| 690 | 7 | |a Systemic lupus erythematous |2 nationallicence | |
| 690 | 7 | |a Pharmacokinetics |2 nationallicence | |
| 690 | 7 | |a Pharmacodynamics |2 nationallicence | |
| 700 | 1 | |a Chudasama |D Vaishali |u Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA |4 aut | |
| 700 | 1 | |a Zutshi |D Anup |u Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA |4 aut | |
| 700 | 1 | |a Singh |D Pratap |u Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA |4 aut | |
| 700 | 1 | |a Abraham |D Anson |u Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA |4 aut | |
| 700 | 1 | |a Mager |D Donald |u Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA |4 aut | |
| 700 | 1 | |a Harrold |D John |u Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA |4 aut | |
| 773 | 0 | |t Journal of Pharmacokinetics and Pharmacodynamics |d Springer US; http://www.springer-ny.com |g 42/1(2015-02-01), 1-18 |x 1567-567X |q 42:1<1 |1 2015 |2 42 |o 10928 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s10928-014-9401-1 |q text/html |z Onlinezugriff via DOI |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-springer | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s10928-014-9401-1 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Chudasama |D Vaishali |u Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Zutshi |D Anup |u Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Singh |D Pratap |u Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Abraham |D Anson |u Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Mager |D Donald |u Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Harrold |D John |u Translational Modeling & Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 700 Main St, 02139, Cambridge, MA, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Pharmacokinetics and Pharmacodynamics |d Springer US; http://www.springer-ny.com |g 42/1(2015-02-01), 1-18 |x 1567-567X |q 42:1<1 |1 2015 |2 42 |o 10928 | ||