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Journal of Pharmacokinetics and Pharmacodynamics

, Volume 42, Issue 5, pp 541–552 | Cite as

Physiologically-based pharmacokinetic modeling of target-mediated drug disposition of bortezomib in mice

  • Li Zhang
  • Donald E. Mager
Original Paper

Abstract

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 1 mg/kg) were administrated to BALB/c mice, with blood and tissue samples obtained over 144 h, 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 (1.3 mg/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.

Keywords

Bortezomib Physiologically-based pharmacokinetics Proteasome binding Target-mediated drug disposition 

Notes

Acknowledgments

This work was supported by National Institutes of Health [Grant GM57980]. We thank Ms. Donna Ruszaj for her valuable technical assistance in developing the LC/MS/MS assay.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest that would influence this work.

Supplementary material

10928_2015_9445_MOESM1_ESM.docx (108 kb)
Supplementary material 1 (DOCX 108 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, University at BuffaloState University of New YorkBuffaloUSA

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