Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 1, pp 57–67 | Cite as

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

  • Donna E. Reece
  • Dan Sullivan
  • Sagar Lonial
  • Ann F. Mohrbacher
  • Gurkamal Chatta
  • Chaim Shustik
  • Howard BurrisIII
  • Karthik Venkatakrishnan
  • Rachel Neuwirth
  • William J. Riordan
  • Michael Karol
  • Lisa L. von Moltke
  • Milin Acharya
  • Peter Zannikos
  • A. Keith Stewart
Original Article

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

Pharmacodynamics Pharmacokinetics Bortezomib Multiple myeloma Proteasome inhibition 

Notes

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.

Supplementary material

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

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Donna E. Reece
    • 1
  • Dan Sullivan
    • 2
  • Sagar Lonial
    • 3
  • Ann F. Mohrbacher
    • 4
  • Gurkamal Chatta
    • 5
  • Chaim Shustik
    • 6
  • Howard BurrisIII
    • 7
  • Karthik Venkatakrishnan
    • 8
  • Rachel Neuwirth
    • 8
  • William J. Riordan
    • 8
  • Michael Karol
    • 8
    • 11
  • Lisa L. von Moltke
    • 8
  • Milin Acharya
    • 9
  • Peter Zannikos
    • 9
  • A. Keith Stewart
    • 10
  1. 1.Department of Medical Oncology and HematologyPrincess Margaret HospitalTorontoCanada
  2. 2.H. Lee Moffitt Cancer CenterTampaUSA
  3. 3.Emory University HospitalAtlantaUSA
  4. 4.University of Southern CaliforniaLos AngelesUSA
  5. 5.University of Pittsburgh Cancer InstitutePittsburghUSA
  6. 6.Royal Victoria HospitalMontrealCanada
  7. 7.The Sarah Cannon Cancer CenterNashvilleUSA
  8. 8.Millennium Pharmaceuticals IncCambridgeUSA
  9. 9.Johnson & Johnson Pharmaceutical Research & Development, L.L.CRaritanUSA
  10. 10.Mayo ClinicScottsdaleUSA
  11. 11.Synta Pharmaceuticals CorpLexingtonUSA

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