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
First Online:
Received:
Accepted:

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 
This is a preview of subscription content, log in to check access.

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)

References

  1. 1.
    Millennium Pharmaceuticals Inc. (2008) VELCADE® (bortezomib) for Injection. Prescribing information. Cambridge, MA, USA; Issued June 2008, Rev 9Google Scholar
  2. 2.
    Janssen-Cilag International NV (2009) VELCADE® (bortezomib). Summary of product characteristics, Beerse, BelgiumGoogle Scholar
  3. 3.
    Ciechanover A, Schwartz AL (1998) The ubiquitin-proteasome pathway: the complexity and myriad functions of proteins death. Proc Natl Acad Sci USA 95:2727–2730CrossRefPubMedGoogle Scholar
  4. 4.
    Boccadoro M, Morgan G, Cavenagh J (2005) Preclinical evaluation of the proteasome inhibitor bortezomib in cancer therapy. Cancer Cell Int 5:18CrossRefPubMedGoogle Scholar
  5. 5.
    Adams J (2004) The proteasome: a suitable antineoplastic target. Nat Rev Cancer 4:349–360CrossRefPubMedGoogle Scholar
  6. 6.
    Cavo M, Tacchetti P, Patriarca F et al (2008) Superior complete response rate and progression-free survival after autologous transplantation with up-front Velcade-thalidomide-dexamethasone compared with thalidomide-dexamethasone in newly diagnosed multiple myeloma. Blood 112:65aGoogle Scholar
  7. 7.
    Harousseau JL, Mathiot C, Attal M et al (2008) Bortezomib/dexamethasone versus VAD as induction prior to autologous stem cell transplantion (ASCT) in previously untreated multiple myeloma (MM): Updated data from IFM 2005/01 trial. J Clin Oncol 26:455sCrossRefGoogle Scholar
  8. 8.
    Richardson PG, Mitsiades C, Schlossman R et al (2008) Bortezomib in the front-line treatment of multiple myeloma. Expert Rev Anticancer Ther 8:1053–1072CrossRefPubMedGoogle Scholar
  9. 9.
    San Miguel JF, Schlag R, Khuageva NK et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906–917CrossRefPubMedGoogle Scholar
  10. 10.
    Jagannath S, Barlogie B, Berenson J et al (2004) A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165–172CrossRefPubMedGoogle Scholar
  11. 11.
    Jagannath S, Barlogie B, Berenson JR et al (2008) Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol 143:537–540PubMedGoogle Scholar
  12. 12.
    Richardson PG, Barlogie B, Berenson J et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609–2617CrossRefPubMedGoogle Scholar
  13. 13.
    Richardson PG, Sonneveld P, Schuster MW et al (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487–2498CrossRefPubMedGoogle Scholar
  14. 14.
    Richardson PG, Mitsiades C, Ghobrial I, Anderson K (2006) Beyond single-agent bortezomib: combination regimens in relapsed multiple myeloma. Curr Opin Oncol 18:598–608CrossRefPubMedGoogle Scholar
  15. 15.
    Richardson PG, Sonneveld P, Schuster M et al (2007) Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 110:3557–3560CrossRefPubMedGoogle Scholar
  16. 16.
    San Miguel JF, Schlag R, Khuageva NK et al (2008) Updated follow-up and results of subsequent therapy in the phase III VISTA trial: bortezomib plus melphalan-prednisone versus melphalan-prednisone in newly diagnosed multiple myeloma. Blood 112:242aGoogle Scholar
  17. 17.
    Adams J, Kauffman M (2004) Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest 22:304–311CrossRefPubMedGoogle Scholar
  18. 18.
    Papandreou CN, Daliani DD, Nix D et al (2004) Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 22:2108–2121CrossRefPubMedGoogle Scholar
  19. 19.
    Labutti J, Parsons I, Huang R, Miwa G, Gan LS, Daniels JS (2006) Oxidative deboronation of the peptide boronic acid proteasome inhibitor bortezomib: contributions from reactive oxygen species in this novel cytochrome P450 reaction. Chem Res Toxicol 19:539–546CrossRefPubMedGoogle Scholar
  20. 20.
    Pekol T, Daniels JS, Labutti J et al (2005) Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. Drug Metab Dispos 33:771–777CrossRefPubMedGoogle Scholar
  21. 21.
    Uttamsingh V, Lu C, Miwa G, Gan LS (2005) Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab Dispos 33:1723–1728CrossRefPubMedGoogle Scholar
  22. 22.
    Lightcap ES, McCormack TA, Pien CS, Chau V, Adams J, Elliott PJ (2000) Proteasome inhibition measurements: clinical application. Clin Chem 46:673–683PubMedGoogle Scholar
  23. 23.
    Bladé J, Samson D, Reece D et al (1998) Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma subcommittee of the EBMT. European group for blood and marrow transplant. Br J Haematol 102:1115–1123CrossRefPubMedGoogle Scholar
  24. 24.
    Calhoun EA, Welshman EE, Chang CH et al (2003) Psychometric evaluation of the functional assessment of cancer therapy/gynecologic oncology group-neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer 13:741–748CrossRefPubMedGoogle Scholar
  25. 25.
    Moreau P, Coiteux V, Hulin C et al (2008) Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma. Haematologica 93:1908–1911CrossRefPubMedGoogle Scholar
  26. 26.
    Hamilton AL, Eder JP, Pavlick AC et al (2005) Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle. J Clin Oncol 23:6107–6116CrossRefPubMedGoogle Scholar
  27. 27.
    Popat R, Oakervee HE, Hallam S et al (2008) Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: updated results after long-term follow-up. Br J Haematol 141:512–516CrossRefPubMedGoogle Scholar
  28. 28.
    Lonial S, Richardson PG, San MJ et al (2008) Characterisation of haematological profiles and low risk of thromboembolic events with bortezomib in patients with relapsed multiple myeloma. Br J Haematol 143:222–229CrossRefPubMedGoogle Scholar
  29. 29.
    Richardson PG, Briemberg H, Jagannath S et al (2006) Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24:3113–3120CrossRefPubMedGoogle Scholar
  30. 30.
    Richardson PG, Sonneveld P, Schuster MW et al (2009) Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol 144:895–903CrossRefPubMedGoogle Scholar

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

Personalised recommendations