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

Authors

  • Ticiana B. Leal
    • University of Wisconsin Carbone Cancer Center
  • Scot C. Remick
    • Comprehensive Cancer Center at University Hospitals of Cleveland and Case Western Reserve University
  • Chris H. Takimoto
    • Institute for Drug Development, Cancer Therapy and Research CenterUniversity of Texas Health Science Center
  • Ramesh K. Ramanathan
    • University of Pittsburgh Cancer Institute
  • Angela Davies
    • UC Davis Cancer Center
  • Merrill J. Egorin
    • University of Pittsburgh Cancer Institute
  • Anne Hamilton
    • Sydney Cancer Centre
  • Patricia A. LoRusso
    • Wayne State University
  • Stephen Shibata
    • City of Hope National Medical Center
  • Heinz-Josef Lenz
    • USC/Norris Comprehensive Cancer Center
  • James Mier
    • Beth Israel Deaconess Medical Center
  • John Sarantopoulos
    • Institute for Drug Development, Cancer Therapy and Research CenterUniversity of Texas Health Science Center
  • Sridhar Mani
    • Montefiore HospitalAlbert Einstein College of Medicine
  • John J. Wright
    • Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and DiagnosisNational Cancer Institute
  • S. Percy Ivy
    • Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and DiagnosisNational Cancer Institute
  • Rachel Neuwirth
    • Millennium Pharmaceuticals, Inc.
  • Lisa von Moltke
    • Millennium Pharmaceuticals, Inc.
  • Karthik Venkatakrishnan
    • Millennium Pharmaceuticals, Inc.
    • University of Wisconsin Carbone Cancer Center
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

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