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Clinical Pharmacokinetics

, Volume 58, Issue 2, pp 157–168 | Cite as

Clinical Pharmacokinetics and Pharmacodynamics of Bortezomib

  • Carlyn Rose C. Tan
  • Saif Abdul-Majeed
  • Brittany Cael
  • Stefan K. BartaEmail author
Review Article

Abstract

Proteasome inhibitors disrupt multiple pathways in cells and the bone marrow microenvironment, resulting in apoptosis and inhibition of cell-cycle progression, angiogenesis, and proliferation. Bortezomib is a first-in-class proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma after one prior therapy. It is also effective in other plasma cell disorders and non-Hodgkin lymphomas. The main mechanism of action of bortezomib is to inhibit the chymotrypsin-like site of the 20S proteolytic core within the 26S proteasome, thereby inducing cell-cycle arrest and apoptosis. The pharmacokinetic profile of intravenous bortezomib is characterized by a two-compartment model with a rapid initial distribution phase followed by a longer elimination phase and a large volume of distribution. Bortezomib is available for subcutaneous and intravenous administration. Pharmacokinetic studies comparing subcutaneous and intravenous bortezomib demonstrated that systemic exposure was equivalent for both routes; pharmacodynamic parameters of 20S proteasome inhibition were also similar. Renal impairment does not influence the intrinsic pharmacokinetics of bortezomib. However, moderate or severe hepatic impairment causes an increase in plasma concentrations of bortezomib. Therefore, patients with moderate or severe hepatic impairment should start at a reduced dose. Because bortezomib undergoes extensive metabolism by hepatic cytochrome P450 3A4 and 2C19 enzymes, certain strong cytochrome P450 3A4 inducers and inhibitors can also alter the systemic exposure of bortezomib. This article critically reviews and summarizes the clinical pharmacokinetics and pharmacodynamics of bortezomib at various dosing levels and routes of administration as well as in specific patient subsets. In addition, we discuss the clinical efficacy and safety of bortezomib.

Notes

Compliance with Ethical Standards

Funding

No sources of funding were used to assist in the preparation of this review.

Conflict of interest

CRT, SAM, and BC have no conflicts of interest directly relevant to the content of this review. SKB has received research support from Merck, Celgene, Seattle Genetics, Takeda, and Bayer and has received fees for participation in an independent Data and Safety Monitoring Board (DSMB) for Janssen.

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Carlyn Rose C. Tan
    • 1
  • Saif Abdul-Majeed
    • 2
  • Brittany Cael
    • 3
  • Stefan K. Barta
    • 1
    Email author
  1. 1.Department of Hematology/OncologyFox Chase Cancer CenterPhiladelphiaUSA
  2. 2.Office of Clinical ResearchFox Chase Cancer CenterPhiladelphiaUSA
  3. 3.Department of Pharmacy, Bone Marrow Transplant ProgramJeanes HospitalPhiladelphiaUSA

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