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A Translational Physiologically Based Pharmacokinetics/Pharmacodynamics Framework of Target-Mediated Disposition, Target Inhibition and Drug–Drug Interactions of Bortezomib

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Abstract

Bortezomib is a potent 20S proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma. Despite the extensive clinical use of bortezomib, the mechanism of the complex time-dependent pharmacokinetics of bortezomib has not been fully investigated in context of its pharmacodynamics (PD) and drug–drug interaction (DDI) profiles. Here, we aimed to develop a mechanistic physiologically based (PB) PK/PD model to project PK, blood target inhibition and DDI of bortezomib in patients. A minimal PBPK/PD model consisting of six compartments was constructed using a bottom–up approach with pre-clinical data and human physiological parameters. Specifically, the target-mediated drug disposition (TMDD) of bortezomib in red blood cells (RBC), which determines target inhibition in blood, was characterized by incorporating the proteasome binding affinity of bortezomib and the proteasome concentration in RBC. The hepatic clearance and fraction metabolized by different CYP isoforms were estimated from in vitro metabolism and phenotyping experiments. The established model adequately characterized the multi-exponential and time-dependent plasma pharmacokinetics, target binding and blood proteasome inhibition of bortezomib. Further, the model was able to accurately predict the impact of a strong CYP3A inducer (rifampicin) and inhibitor (ketoconazole) on bortezomib exposure. In conclusion, the mechanistic PBPK/PD model successfully described the complex pharmacokinetics, target inhibition and DDIs of bortezomib in patients. This study illustrates the importance of incorporating target biology, drug–target interactions and in vitro clearance parameters into mechanistic PBPK/PD models and the utility of such models for pharmacokinetic, pharmacodynamic and DDI predictions.

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Funding

This work was funded by Takeda Pharmaceuticals International.

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Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International, Co., 35 Landsdowne Street, Cambridge, Massachusetts, USA

    Shinji Iwasaki, Andy Zhu & Cindy Xia

  2. Quantitative Clinical Pharmacology, Takeda Pharmaceuticals International, Co., 35 Landsdowne Street, Cambridge, Massachusetts, USA

    Michael Hanley & Karthik Venkatakrishnan

Authors
  1. Shinji Iwasaki
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  2. Andy Zhu
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  3. Michael Hanley
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  4. Karthik Venkatakrishnan
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  5. Cindy Xia
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Corresponding author

Correspondence to Shinji Iwasaki.

Ethics declarations

All animal procedures were approved by the Institutional Animal Care and Use Committee of the contract research organization.

Conflict of Interest

The authors declare that they have no conflicts of interest. All authors were employees of Takeda Pharmaceuticals International Company when the study was performed.

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Electronic Supplementary Material

Supplemental Fig. 1

Blood concentration-time profile of bortezomib in monkeys after intravenous injection at a dose of 0.1 mg/kg/dose on Day 1, 4, 8, 11, 22, 25, 29, 32, 43, 46, 50, 53, 64, 67, 71 and 74. Symbols represent the individual observed values (n = 6) and lines indicate the simulated profiles (PNG 7059 kb)

Supplemental Fig. 2

Mean time course of (A) plasma concentration, (B) blood concentration and (C) blood proteasome inhibition of bortezomib after the third dosing in cycle 1 and 2 at a dose of 1.3 mg/m2. Symbols represent the observed values (mean ± S.D., n = 17 for plasma and blood concentration, and n = 15 for blood proteasome inhibition) from study CAN-1001. Dashed lines indicate the simulated profiles using default Bmax value. Solid lines indicate the simulated profiles using 1.4-fold higher Bmax value (PNG 19453 kb)

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Iwasaki, S., Zhu, A., Hanley, M. et al. A Translational Physiologically Based Pharmacokinetics/Pharmacodynamics Framework of Target-Mediated Disposition, Target Inhibition and Drug–Drug Interactions of Bortezomib. AAPS J 22, 66 (2020). https://doi.org/10.1208/s12248-020-00448-x

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