caa a22 4500 60553411X CHVBK 20210128100841.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s10928-015-9445-x doi (NATIONALLICENCE)springer-10.1007/s10928-015-9445-x Physiologically-based pharmacokinetic modeling of target-mediated drug disposition of bortezomib in mice [Elektronische Daten] [Li Zhang, Donald Mager] Bortezomib is a reversible proteasome inhibitor with potent antineoplastic activity that exhibits dose- and time-dependent pharmacokinetics (PK). Proteasome-mediated bortezomib disposition is proposed as the primary source of its nonlinear and apparent nonstationary PK behavior. Single intravenous (IV) doses of bortezomib (0.25 and 1mg/kg) were administrated to BALB/c mice, with blood and tissue samples obtained over 144h, which were analyzed by LC/MS/MS. A physiologically based pharmacokinetic (PBPK) model incorporating tissue drug-target binding was developed to test the hypothesis of proteasome-mediated bortezomib disposition. The final model reasonably captured bortezomib plasma and tissue PK profiles, and parameters were estimated with good precision. The rank-order of model estimated tissue target density correlated well with experimentally measured proteasome concentrations reported in the literature, supporting the hypothesis that binding to proteasome influences bortezomib disposition. The PBPK model was further scaled-up to humans to assess the similarity of bortezomib disposition among species. Human plasma bortezomib PK profiles following multiple IV dosing (1.3mg/m2) on days 1, 4, 8, and 11 were simulated by appropriately scaling estimated mouse parameters. Simulated and observed bortezomib concentrations after multiple dosing were in good agreement, suggesting target-mediated bortezomib disposition is likely for both mice and humans. Furthermore, the model predicts that renal impairment should exert minimal influence on bortezomib exposure in humans, confirming that bortezomib dose adjustment is not necessary for patients with renal impairment. Springer Science+Business Media New York, 2015 Bortezomib nationallicence Physiologically-based pharmacokinetics nationallicence Proteasome binding nationallicence Target-mediated drug disposition nationallicence Zhang Li Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 14214, Buffalo, NY, USA aut Mager Donald Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 14214, Buffalo, NY, USA aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/5(2015-10-01), 541-552 1567-567X 42:5<541 2015 42 10928 https://doi.org/10.1007/s10928-015-9445-x 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/s10928-015-9445-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Zhang Li Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 14214, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Mager Donald Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 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), 541-552 1567-567X 42:5<541 2015 42 10928