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

Research output: Contribution to journalArticle

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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/m 2 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 m 2 into five cohorts: normal renal function (≥60 ml/min/1.73 m 2); mild dysfunction (40-59 ml/min/1.73 m 2); moderate dysfunction (20-39 ml/min/1.73 m 2); severe dysfunction (<20 ml/min/1.73 m 2); 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/m 2 dose was well tolerated in all patients with CrCl ≥20 ml/min/1.73 m 2; 0.7 mg/m 2 was tolerated in three patients with severe renal dysfunction (<20 ml/min/1.73 m 2). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m 2 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/m 2 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.

Original languageEnglish (US)
Pages (from-to)1439-1447
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume68
Issue number6
DOIs
StatePublished - Dec 2011

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National Cancer Institute (U.S.)
Pharmacology
Kidney
Neoplasms
Dialysis
Pharmacodynamics
Creatinine
Pharmacokinetics
Bortezomib
Proteasome Endopeptidase Complex
Extrapolation
Toxicity
Blood
Maximum Tolerated Dose
Body Surface Area
Plasmas
Population

Keywords

  • Bortezomib
  • Pharmacodynamics
  • Pharmacokinetics
  • Renal function
  • Toxicity

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function : A National Cancer Institute Organ Dysfunction Working Group Study. / Leal, Ticiana B.; Remick, Scot C.; Takimoto, Chris H.; Ramanathan, Ramesh K.; Davies, Angela; Egorin, Merrill J.; Hamilton, Anne; Lorusso, Patricia A.; Shibata, Stephen; Lenz, Heinz Josef; Mier, James; Sarantopoulos, John; Mani, Sridhar; Wright, John J.; Ivy, S. Percy; Neuwirth, Rachel; Von Moltke, Lisa; Venkatakrishnan, Karthik; Mulkerin, Daniel.

In: Cancer Chemotherapy and Pharmacology, Vol. 68, No. 6, 12.2011, p. 1439-1447.

Research output: Contribution to journalArticle

Leal, TB, Remick, SC, Takimoto, CH, Ramanathan, RK, Davies, A, Egorin, MJ, Hamilton, A, Lorusso, PA, Shibata, S, Lenz, HJ, Mier, J, Sarantopoulos, J, Mani, S, Wright, JJ, Ivy, SP, Neuwirth, R, Von Moltke, L, Venkatakrishnan, K & Mulkerin, D 2011, 'Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: A National Cancer Institute Organ Dysfunction Working Group Study', Cancer Chemotherapy and Pharmacology, vol. 68, no. 6, pp. 1439-1447. https://doi.org/10.1007/s00280-011-1637-5
Leal, Ticiana B. ; Remick, Scot C. ; Takimoto, Chris H. ; Ramanathan, Ramesh K. ; Davies, Angela ; Egorin, Merrill J. ; Hamilton, Anne ; Lorusso, Patricia A. ; Shibata, Stephen ; Lenz, Heinz Josef ; Mier, James ; Sarantopoulos, John ; Mani, Sridhar ; Wright, John J. ; Ivy, S. Percy ; Neuwirth, Rachel ; Von Moltke, Lisa ; Venkatakrishnan, Karthik ; Mulkerin, Daniel. / Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function : A National Cancer Institute Organ Dysfunction Working Group Study. In: Cancer Chemotherapy and Pharmacology. 2011 ; Vol. 68, No. 6. pp. 1439-1447.
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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/m 2 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 m 2 into five cohorts: normal renal function (≥60 ml/min/1.73 m 2); mild dysfunction (40-59 ml/min/1.73 m 2); moderate dysfunction (20-39 ml/min/1.73 m 2); severe dysfunction (<20 ml/min/1.73 m 2); 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/m 2 dose was well tolerated in all patients with CrCl ≥20 ml/min/1.73 m 2; 0.7 mg/m 2 was tolerated in three patients with severe renal dysfunction (<20 ml/min/1.73 m 2). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m 2 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/m 2 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.",
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T1 - Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function

T2 - A National Cancer Institute Organ Dysfunction Working Group Study

AU - Leal, Ticiana B.

AU - Remick, Scot C.

AU - Takimoto, Chris H.

AU - Ramanathan, Ramesh K.

AU - Davies, Angela

AU - Egorin, Merrill J.

AU - Hamilton, Anne

AU - Lorusso, Patricia A.

AU - Shibata, Stephen

AU - Lenz, Heinz Josef

AU - Mier, James

AU - Sarantopoulos, John

AU - Mani, Sridhar

AU - Wright, John J.

AU - Ivy, S. Percy

AU - Neuwirth, Rachel

AU - Von Moltke, Lisa

AU - Venkatakrishnan, Karthik

AU - Mulkerin, Daniel

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N2 - 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/m 2 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 m 2 into five cohorts: normal renal function (≥60 ml/min/1.73 m 2); mild dysfunction (40-59 ml/min/1.73 m 2); moderate dysfunction (20-39 ml/min/1.73 m 2); severe dysfunction (<20 ml/min/1.73 m 2); 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/m 2 dose was well tolerated in all patients with CrCl ≥20 ml/min/1.73 m 2; 0.7 mg/m 2 was tolerated in three patients with severe renal dysfunction (<20 ml/min/1.73 m 2). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m 2 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/m 2 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.

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KW - Bortezomib

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Renal function

KW - Toxicity

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