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

University of Wisconsin Carbone Cancer Center, 600 Highland Ave, Madison, WI 53792, USA.
Cancer Chemotherapy and Pharmacology (Impact Factor: 2.77). 04/2011; 68(6):1439-47. DOI: 10.1007/s00280-011-1637-5
Source: PubMed

ABSTRACT 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.
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.
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.
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.

Download full-text


Available from: Ticiana Leal, Sep 28, 2015
20 Reads
  • Source
    • "Patients with asymptomatic renal dysfunction might not have increased drug-related adverse events with the agents that are predominantly eliminated via other routes, and therefore, less likely to complicate assessment of toxic effects. Multiple Phase I trials conducted exclusively in cancer patients with renal dysfunction, have reinforced the notion that the MTD in these patients is either the same or up to 25% lower than the previously established MTD [4] [10] [11]. To further illustrate the point, imatinib was originally granted accelerated approval for the treatment of advanced or metastatic gastrointestinal stromal tumour in 2002. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Since the inception of Phase I clinical trials in cancer, patients with renal dysfunc-tion have commonly been excluded from participation because of a poor outlook. Most cancer drugs are approved with limited information on the pharmacokinetics and/or pharmacody-namics of the drugs in patients with renal dysfunction, and no formal renal dysfunction study is ever undertaken. Patients with asymptomatic mild to moderate renal dysfunction pose an increasingly frequent challenge for clinicians. In this paper, we discuss that a subset of patients with asymptomatic mild to moderate renal impairment might be appropriately entered into selected Phase I trials. This will provide physicians timely data of the new agents in this patient population and increase patients' access to experimental treatments.
    European Journal of Cancer 09/2014; 50(17). DOI:10.1016/j.ejca.2014.09.001 · 5.42 Impact Factor
  • Source
    • "With the advent of rapid acting novel agents showing improved renal recovery, myeloma response, and over-all prognosis, prompt chemoinitiation with bortezomib-based regimen has become the standard strategy [42]. Sometimes, patients might have been already initiated on hemodialysis for advanced RF with a pending or established diagnosis of MM; in this dialysis-dependent population as well, bortezomib was shown to be well tolerated [43, 44] compared to other conventional chemoagents [45, 46] and, furthermore, novel agents in combination with high-dose dexamethasone improved renal function rapidly to become independent of dialysis sooner [23, 44]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Renal failure (RF) reversal in multiple myeloma (MM) is associated with an improved prognosis. Light chain myeloma, serum creatinine (SCr) > 4 mg/dL, extensive proteinuria, early infections, and certain renal biopsy findings are associated with lower rates of RF reversal. Our patient is a 67-year-old female with multiple poor prognostic factors for RF reversal who demonstrated a rapid renal response with bortezomib and dexamethasone (BD) regimen. She presented initially with altered mental status. On exam, she appeared lethargic and dehydrated and had generalized tenderness. She had been taking ibuprofen as needed for pain for a few weeks. Labs showed a white cell count-18,900/μL with no bandemia, hemoglobin 10.8 gm/dL, potassium-6.7 mEq/L, bicarbonate-15 mEq/L, blood urea nitrogen-62 mg/dL, SCr-5.6 mg/dL (baseline: 1.10), and corrected calcium-11.8 mg/dL. A rapid flu test was positive. Imaging studies were unremarkable. Her EKG showed sinus tachycardia and her urinalysis was unremarkable. The unexplained RF in an elderly individual in conjunction with hypercalcemia and anemia prompted a MM work-up; eventually, lambda variant MM was diagnosed. An immediate (4 days) renal response defined as 50% reduction in SCr was noticed after initiation of the BD regimen.
    06/2014; 2014:940171. DOI:10.1155/2014/940171
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to evaluate long-term platinum retention in patients treated with cisplatin and oxaliplatin. 45 patients, treated 8-75 months before participating in this study, were included. Platinum levels in plasma and plasma ultrafiltrate (pUF) were determined. In addition, the reactivity of platinum species in pUF was evaluated. Relationships between platinum retention and possible determinants were evaluated. Platinum plasma concentrations ranged between 142-2.99 x 10(3) ng/L. Up to 24% of plasma platinum was recovered in pUF. No platinum-DNA adducts in peripheral blood mononuclear cells (PBMCs) could be detected. Ex vivo incubation of DNA with pUF of patients revealed that up to 10% of the reactivity of platinum species was retained. Protein binding proceeded during sample storage. Sodium thiosulfate (STS) appeared to release platinum from the plasma proteins. Platinum levels were related to time, dose, STS co-administration, and glomerular filtration rates (GFR). Our data suggest that plasma platinum levels are related to time, age, dose, GFR, and STS use. Platinum in plasma, probably, represent platinum eliminated from regenerating tissue. Platinum species in pUF were partly present in a reactive form. The effects of the reactivity on long-term consequences of Pt-containing chemotherapy, however, remains to be established.
    BMC Clinical Pharmacology 10/2008; 8(1):7. DOI:10.1186/1472-6904-8-7 · 1.36 Impact Factor
Show more