Original Article

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. LealAffiliated withUniversity of Wisconsin Carbone Cancer Center
  • , Scot C. RemickAffiliated withComprehensive Cancer Center at University Hospitals of Cleveland and Case Western Reserve University
  • , Chris H. TakimotoAffiliated withInstitute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center
  • , Ramesh K. RamanathanAffiliated withUniversity of Pittsburgh Cancer Institute
  • , Angela DaviesAffiliated withUC Davis Cancer Center
  • , Merrill J. EgorinAffiliated withUniversity of Pittsburgh Cancer Institute
  • , Anne HamiltonAffiliated withSydney Cancer Centre
  • , Patricia A. LoRussoAffiliated withWayne State University
  • , Stephen ShibataAffiliated withCity of Hope National Medical Center
    • , Heinz-Josef LenzAffiliated withUSC/Norris Comprehensive Cancer Center
    • , James MierAffiliated withUniversity of Wisconsin Carbone Cancer CenterBeth Israel Deaconess Medical Center
    • , John SarantopoulosAffiliated withInstitute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center
    • , Sridhar ManiAffiliated withUniversity of Wisconsin Carbone Cancer CenterMontefiore Hospital, Albert Einstein College of Medicine
    • , John J. WrightAffiliated withUniversity of Wisconsin Carbone Cancer CenterInvestigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute
    • , S. Percy IvyAffiliated withUniversity of Wisconsin Carbone Cancer CenterInvestigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute
    • , Rachel NeuwirthAffiliated withUniversity of Wisconsin Carbone Cancer CenterMillennium Pharmaceuticals, Inc.
    • , Lisa von MoltkeAffiliated withUniversity of Wisconsin Carbone Cancer CenterMillennium Pharmaceuticals, Inc.
    • , Karthik VenkatakrishnanAffiliated withUniversity of Wisconsin Carbone Cancer CenterMillennium Pharmaceuticals, Inc.
    • , Daniel MulkerinAffiliated withUniversity of Wisconsin Carbone Cancer Center Email author 

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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 function Bortezomib Toxicity Pharmacokinetics Pharmacodynamics