Physiologically-based pharmacokinetic modeling of target-mediated drug disposition of bortezomib in mice
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| 024 | 7 | 0 | |a 10.1007/s10928-015-9445-x |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s10928-015-9445-x | ||
| 245 | 0 | 0 | |a Physiologically-based pharmacokinetic modeling of target-mediated drug disposition of bortezomib in mice |h [Elektronische Daten] |c [Li Zhang, Donald Mager] |
| 520 | 3 | |a 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. | |
| 540 | |a Springer Science+Business Media New York, 2015 | ||
| 690 | 7 | |a Bortezomib |2 nationallicence | |
| 690 | 7 | |a Physiologically-based pharmacokinetics |2 nationallicence | |
| 690 | 7 | |a Proteasome binding |2 nationallicence | |
| 690 | 7 | |a Target-mediated drug disposition |2 nationallicence | |
| 700 | 1 | |a Zhang |D Li |u Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 14214, Buffalo, NY, USA |4 aut | |
| 700 | 1 | |a Mager |D Donald |u Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 14214, Buffalo, NY, USA |4 aut | |
| 773 | 0 | |t Journal of Pharmacokinetics and Pharmacodynamics |d Springer US; http://www.springer-ny.com |g 42/5(2015-10-01), 541-552 |x 1567-567X |q 42:5<541 |1 2015 |2 42 |o 10928 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s10928-015-9445-x |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/s10928-015-9445-x |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Zhang |D Li |u Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 14214, Buffalo, NY, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Mager |D Donald |u Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 14214, Buffalo, NY, 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 42/5(2015-10-01), 541-552 |x 1567-567X |q 42:5<541 |1 2015 |2 42 |o 10928 | ||