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Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma

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Abstract

Purpose

Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses.

Methods

Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m2, days 1, 4, 8, 11, for up to eight 21-day treatment cycles (n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected.

Results

Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102–112 L/h for first dose; 15–32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m2 group.

Conclusions

Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m2 doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.

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Acknowledgments

The authors would like to acknowledge editorial assistance from Steve Hill and Jane Saunders of FireKite during the development of this manuscript, which was funded by Millennium Pharmaceuticals, Inc. Research was supported in part by Millennium Pharmaceuticals, Inc. and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Conflict of interest statement

DER: consultancy/advisory role for, and research funding from, Millennium Pharmaceuticals and Johnson & Johnson. SL: consultancy/advisory role for Amgen, BMS, Millennium Pharmaceuticals, Ortho-Biotech, Novartis. AFM: Honoraria from Millennium Pharmaceuticals speakers bureau. KV: renumeration from Millennium Pharmaceuticals. RN: renumeration from Millennium Pharmaceuticals. WJR: renumeration from Millennium Pharmaceuticals. MK: renumeration from, and stock ownership of, Millennium Pharmaceuticals. LLVL: renumeration from Millennium Pharmaceuticals. PZ: renumeration from, and stock ownership of, Johnson & Johnson. AKS: consultancy/advisory role for, and research funding from, Millennium Pharmaceuticals. DS, GC, CS, HB, and MA have no disclosures.

Author information

Author notes

  1. Michael Karol

    Present address: Synta Pharmaceuticals Corp, Lexington, MA, USA

Authors and Affiliations

  1. Department of Medical Oncology and Hematology, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada

    Donna E. Reece

  2. H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Dan Sullivan

  3. Emory University Hospital, Atlanta, GA, USA

    Sagar Lonial

  4. University of Southern California, Los Angeles, CA, USA

    Ann F. Mohrbacher

  5. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Gurkamal Chatta

  6. Royal Victoria Hospital, Montreal, QC, Canada

    Chaim Shustik

  7. The Sarah Cannon Cancer Center, Nashville, TN, USA

    Howard Burris III

  8. Millennium Pharmaceuticals Inc, Cambridge, MA, USA

    Karthik Venkatakrishnan, Rachel Neuwirth, William J. Riordan, Michael Karol & Lisa L. von Moltke

  9. Johnson & Johnson Pharmaceutical Research & Development, L.L.C, Raritan, NJ, USA

    Milin Acharya & Peter Zannikos

  10. Mayo Clinic, Scottsdale, AZ, USA

    A. Keith Stewart

Authors
  1. Donna E. Reece
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Corresponding author

Correspondence to Donna E. Reece.

Electronic supplementary material

Supplemental Figure. Patient disposition throughout the study.

Supplementary material 1 (TIFF 157 kb)

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Reece, D.E., Sullivan, D., Lonial, S. et al. Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma. Cancer Chemother Pharmacol 67, 57–67 (2011). https://doi.org/10.1007/s00280-010-1283-3

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  • DOI: https://doi.org/10.1007/s00280-010-1283-3

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