Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 1, pp 57–67

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

Authors

    • Department of Medical Oncology and HematologyPrincess Margaret Hospital
  • Dan Sullivan
    • H. Lee Moffitt Cancer Center
  • Sagar Lonial
    • Emory University Hospital
  • Ann F. Mohrbacher
    • University of Southern California
  • Gurkamal Chatta
    • University of Pittsburgh Cancer Institute
  • Chaim Shustik
    • Royal Victoria Hospital
  • Howard BurrisIII
    • The Sarah Cannon Cancer Center
  • Karthik Venkatakrishnan
    • Millennium Pharmaceuticals Inc
  • Rachel Neuwirth
    • Millennium Pharmaceuticals Inc
  • William J. Riordan
    • Millennium Pharmaceuticals Inc
  • Michael Karol
    • Millennium Pharmaceuticals Inc
    • Synta Pharmaceuticals Corp
  • Lisa L. von Moltke
    • Millennium Pharmaceuticals Inc
  • Milin Acharya
    • Johnson & Johnson Pharmaceutical Research & Development, L.L.C
  • Peter Zannikos
    • Johnson & Johnson Pharmaceutical Research & Development, L.L.C
  • A. Keith Stewart
    • Mayo Clinic
Original Article

DOI: 10.1007/s00280-010-1283-3

Cite this article as:
Reece, D.E., Sullivan, D., Lonial, S. et al. Cancer Chemother Pharmacol (2011) 67: 57. doi:10.1007/s00280-010-1283-3

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.

Keywords

PharmacodynamicsPharmacokineticsBortezomibMultiple myelomaProteasome inhibition

Supplementary material

280_2010_1283_MOESM1_ESM.tif (158 kb)
Supplementary material 1 (TIFF 157 kb)

Copyright information

© Springer-Verlag 2010