caa a22 4500 605534101 CHVBK 20210128100841.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s10928-015-9444-y doi (NATIONALLICENCE)springer-10.1007/s10928-015-9444-y Scale-up of a physiologically-based pharmacokinetic model to predict the disposition of monoclonal antibodies in monkeys [Elektronische Daten] [Patrick Glassman, Yang Chen, Joseph Balthasar] Preclinical assessment of monoclonal antibody (mAb) disposition during drug development often includes investigations in non-human primate models. In many cases, mAb exhibit non-linear disposition that relates to mAb-target binding [i.e., target-mediated disposition (TMD)]. The goal of this work was to develop a physiologically-based pharmacokinetic (PBPK) model to predict non-linear mAb disposition in plasma and in tissues in monkeys. Physiological parameters for monkeys were collected from several sources, and plasma data for several mAbs associated with linear pharmacokinetics were digitized from prior literature reports. The digitized data displayed great variability; therefore, parameters describing inter-antibody variability in the rates of pinocytosis and convection were estimated. For prediction of the disposition of individual antibodies, we incorporated tissue concentrations of target proteins, where concentrations were estimated based on categorical immunohistochemistry scores, and with assumed localization of target within the interstitial space of each organ. Kinetics of target-mAb binding and target turnover, in the presence or absence of mAb, were implemented. The model was then employed to predict concentration versus time data, via Monte Carlo simulation, for two mAb that have been shown to exhibit TMD (2F8 and tocilizumab). Model predictions, performed a priori with no parameter fitting, were found to provide good prediction of dose-dependencies in plasma clearance, the areas under plasma concentration versu time curves, and the time-course of plasma concentration data. This PBPK model may find utility in predicting plasma and tissue concentration versus time data and, potentially, the time-course of receptor occupancy (i.e., mAb-target binding) to support the design and interpretation of preclinical pharmacokinetic-pharmacodynamic investigations in non-human primates. Springer Science+Business Media New York, 2015 Physiologically-based nationallicence Pharmacokinetics nationallicence Monoclonal antibody nationallicence Glassman Patrick Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 452 Kapoor Hall, 14214, Buffalo, NY, USA aut Chen Yang Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 452 Kapoor Hall, 14214, Buffalo, NY, USA aut Balthasar Joseph Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 452 Kapoor Hall, 14214, Buffalo, NY, USA aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/5(2015-10-01), 527-540 1567-567X 42:5<527 2015 42 10928 https://doi.org/10.1007/s10928-015-9444-y 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/s10928-015-9444-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Glassman Patrick Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 452 Kapoor Hall, 14214, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Chen Yang Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 452 Kapoor Hall, 14214, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Balthasar Joseph Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 452 Kapoor Hall, 14214, Buffalo, NY, USA aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/5(2015-10-01), 527-540 1567-567X 42:5<527 2015 42 10928