Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 6, pp 1439–1447

Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study

  • Ticiana B. Leal
  • Scot C. Remick
  • Chris H. Takimoto
  • Ramesh K. Ramanathan
  • Angela Davies
  • Merrill J. Egorin
  • Anne Hamilton
  • Patricia A. LoRusso
  • Stephen Shibata
  • Heinz-Josef Lenz
  • James Mier
  • John Sarantopoulos
  • Sridhar Mani
  • John J. Wright
  • S. Percy Ivy
  • Rachel Neuwirth
  • Lisa von Moltke
  • Karthik Venkatakrishnan
  • Daniel Mulkerin
Original Article

DOI: 10.1007/s00280-011-1637-5

Cite this article as:
Leal, T.B., Remick, S.C., Takimoto, C.H. et al. Cancer Chemother Pharmacol (2011) 68: 1439. doi:10.1007/s00280-011-1637-5
  • 202 Views

Abstract

Purpose

To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population.

Patients and Methods

Sixty-two adult cancer patients received intravenous bortezomib at 0.7–1.5 mg/m2 on days 1, 4, 8, and 11 every 3 weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73 m2 into five cohorts: normal renal function (≥60 ml/min/1.73 m2); mild dysfunction (40–59 ml/min/1.73 m2); moderate dysfunction (20–39 ml/min/1.73 m2); severe dysfunction (<20 ml/min/1.73 m2); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed.

Results

Bortezomib escalation to the standard 1.3 mg/m2 dose was well tolerated in all patients with CrCl ≥20 ml/min/1.73 m2; 0.7 mg/m2 was tolerated in three patients with severe renal dysfunction (<20 ml/min/1.73 m2). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m2 in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function.

Conclusion

Bortezomib 1.3 mg/m2 is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.

Keywords

Renal functionBortezomibToxicityPharmacokineticsPharmacodynamics

Supplementary material

280_2011_1637_MOESM1_ESM.doc (340 kb)
Supplementary material 1 (DOC 340 kb)

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ticiana B. Leal
    • 1
  • Scot C. Remick
    • 2
  • Chris H. Takimoto
    • 3
  • Ramesh K. Ramanathan
    • 4
  • Angela Davies
    • 5
  • Merrill J. Egorin
    • 4
  • Anne Hamilton
    • 6
  • Patricia A. LoRusso
    • 7
  • Stephen Shibata
    • 8
  • Heinz-Josef Lenz
    • 9
  • James Mier
    • 10
  • John Sarantopoulos
    • 3
  • Sridhar Mani
    • 11
  • John J. Wright
    • 12
  • S. Percy Ivy
    • 12
  • Rachel Neuwirth
    • 13
  • Lisa von Moltke
    • 13
  • Karthik Venkatakrishnan
    • 13
  • Daniel Mulkerin
    • 1
  1. 1.University of Wisconsin Carbone Cancer CenterMadisonUSA
  2. 2.Comprehensive Cancer Center at University Hospitals of Cleveland and Case Western Reserve UniversityClevelandUSA
  3. 3.Institute for Drug Development, Cancer Therapy and Research CenterUniversity of Texas Health Science CenterSan AntonioUSA
  4. 4.University of Pittsburgh Cancer InstitutePittsburghUSA
  5. 5.UC Davis Cancer CenterSacramentoUSA
  6. 6.Sydney Cancer CentreSydneyAustralia
  7. 7.Wayne State UniversityDetroitUSA
  8. 8.City of Hope National Medical CenterDuarteUSA
  9. 9.USC/Norris Comprehensive Cancer CenterLos AngelesUSA
  10. 10.Beth Israel Deaconess Medical CenterBostonUSA
  11. 11.Montefiore HospitalAlbert Einstein College of MedicineBronxUSA
  12. 12.Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaUSA
  13. 13.Millennium Pharmaceuticals, Inc.CambridgeUSA