Physiologically-based pharmacokinetic modeling of target-mediated drug disposition of bortezomib in mice
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.
KeywordsBortezomib Physiologically-based pharmacokinetics Proteasome binding Target-mediated drug disposition
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.
- 5.Bross PF, Kane R, Farrell AT, Abraham S, Benson K, Brower ME, Bradley S, Gobburu JV, Goheer A, Lee SL, Leighton J, Liang CY, Lostritto RT, McGuinn WD, Morse DE, Rahman A, Rosario LA, Verbois SL, Williams G, Wang YC, Pazdur R (2004) Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res 10:3954–3964CrossRefPubMedGoogle Scholar
- 8.Hemeryck A, Geerts R, Monbaliu J, Hassler S, Verhaeghe T, Diels L, Verluyten W, van Beijsterveldt L, Mamidi RN, Janssen C, De Coster R (2007) Tissue distribution and depletion kinetics of bortezomib and bortezomib-related radioactivity in male rats after single and repeated intravenous injection of 14 C-bortezomib. Cancer Chemother Pharmacol 60:777–787CrossRefPubMedGoogle Scholar
- 9.Akhlaghi F, Monbaliu J, Kadambi V, Li Y (2009) Blood and plasma pharmacokinetics of bortezomib in relation to blood 20S proteasome activity after single and multiple dosing in cynomongolus monkeys. http://www.2009go-acoporg//acop2009 Accessed 9 Oct 2009Google Scholar
- 25.D’Argenio DZ, Schumitzky A, Wang X (2009) ADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. Biomedical Simulation Resource, Los AngelesGoogle Scholar
- 26.Tsu C, Blank J, Garcia K, Liu J, Bruzzese F, Lee E, Cao Y, Bannerman B, Fitzgerald M, Fleming P, Ciavarri J, Hales P, Yu J, Yang Y, Berger A, Sintchak M, Kupperman E, Manfredi M, Dick L (2011) Beyond bortezomib: development of millennium’s next-generation proteasome inhibitors. Mol Cancer Ther. doi: 10.1158/1535-7163TARG-11-C99 Google Scholar
- 27.Reece DE, Sullivan D, Lonial S, Mohrbacher AF, Chatta G, Shustik C, Burris H 3rd, Venkatakrishnan K, Neuwirth R, Riordan WJ, Karol M, von Moltke LL, Acharya M, Zannikos P, Keith Stewart A (2011) Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma. Cancer Chemother Pharmacol 67:57–67PubMedCentralCrossRefPubMedGoogle Scholar
- 28.Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, Yu J, Yang Y, Hales P, Bruzzese F, Liu J, Blank J, Garcia K, Tsu C, Dick L, Fleming P, Yu L, Manfredi M, Rolfe M, Bolen J (2010) Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res 70:1970–1980CrossRefPubMedGoogle Scholar
- 31.Williamson MJ, Blank JL, Bruzzese FJ, Cao Y, Daniels JS, Dick LR, Labutti J, Mazzola AM, Patil AD, Reimer CL, Solomon MS, Stirling M, Tian Y, Tsu CA, Weatherhead GS, Zhang JX, Rolfe M (2006) Comparison of biochemical and biological effects of ML858 (salinosporamide A) and bortezomib. Mol Cancer Ther 5:3052–3061CrossRefPubMedGoogle Scholar
- 33.Nix D, Press R, Wehrman T, Aide R (2003) Tissue distribution and mass balance of bortezomib (Velcade™) in non-human primates. AAPS PharmSci 5:4Google Scholar
- 34.Leal TB, Remick SC, Takimoto CH, Ramanathan RK, Davies A, Egorin MJ, Hamilton A, LoRusso PA, Shibata S, Lenz HJ, Mier J, Sarantopoulos J, Mani S, Wright JJ, Ivy SP, Neuwirth R, von Moltke L, Venkatakrishnan K, Mulkerin D (2011) Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study. Cancer Chemother Pharmacol 68:1439–1447PubMedCentralCrossRefPubMedGoogle Scholar