, Volume 68, Issue 6, pp 1439-1447
Date: 09 Apr 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

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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.

Prior presentations of the study Mulkerin D, Remick S, Ramanathan R et al. A dose-escalating and pharmacologic study of bortezomib in adult cancer patients with impaired renal function. JCO 2006;24:abstract 2032. Poster presentation at 2006 ASCO Annual Meeting. Mulkerin D, Remick S, Takimoto C et al. Safety, tolerability, and pharmacology of bortezomib in cancer patients with impaired renal function, including patients requiring dialysis: results from a prospective phase 1 study. Blood 2007;110:abstract 3477. Poster presentation at 2007 ASH Annual Meeting.