The use of ⁹⁰yttrium-ibritumomab tiuxetan in patients on dialysis: what do we know regarding its pharmacokinetics?

⁹⁰Yttrium-ibritumomab tiuxetan (Zevalin^®; Spectrum Pharmaceuticals) is the first radioimmunotherapy drug approved for cancer by the Food and Drug Administration [1]. Ibritumomab is the murine monoclonal CD20 antibody from which rituximab was made. To make Zevalin, the chelator tiuxetan is linked to the antibody and then ⁹⁰yttrium (⁹⁰Y) attaches tightly to the tiuxetan to form the radioimmunoconjugate. The mechanism of action of Zevalin utilizes the antibody to mediate complement-mediated cytotoxicity along with delivery of the high-energy, short path-length (5 mm) beta irradiation from the ⁹⁰Y to CD20 + lymphoma cells and adjacent microenvironment cells. Zevalin is currently approved for relapsed or refractory low grade or follicular B-cell non-Hodgkin lymphoma (NHL) and as consolidation therapy for patients with newly diagnosed follicular NHL who have achieved a partial or complete response to first-line therapy [2]. Despite numerous clinical trials since the mid-1990s, data regarding its use in patients with end stage renal disease (ESRD) is lacking. Trials have typically excluded patients with reduced renal function (serum creatinine > 2 mg/dL) or did not report the renal function of the patients, providing little information of its pharmacokinetics in patients with severe renal impairment [3–5]. Fukuno et al. [6] in this issue of Leukemia and Lymphoma report a single case of relapsed NHL and ESRD who was treated with Zevalin while on dialysis. The patient had the typical myelosuppression pattern expected with radioimmunotherapy (RIT) and no unexpected non-hematological toxicities.

What do we know about the nephrotoxicity and pharmacokinetics of these important therapeutic agents? Data are available on the pharmacokinetics of the human chimeric antiCD20 antibody rituximab that was derived from the murine ibritumomab in patients with ESRD. Rituximab has been used to reduce allo-antibodies and anti-ABO antibodies prior to kidney transplant [7,8]. Pharmacokinetics studies on a single patient with NHL revealed that rituximab is not dialyzable, and exhibits similar blood levels to patients with normal renal function [9]. No dosage adjustment is thus needed even in patients requiring dialysis. Currently, rituximab is also used in the treatment of several kidney diseases, including antineutrophil cytoplasmic antibody (ANCA) associated vasculitis, membranous nephropathy, lupus nephritis and others [10–13]. No nephrotoxicity has been reported with its use. A faster CD20 recovery was noted in patients with membranous nephropathy when compared with patients who received rituximab for rheumatoid arthritis. Terminal half-life was 11.5 days, which was shorter than the 18.0 days in rheumatoid arthritis, but no association could be found between rituximab levels and proteinuria [10].

Similar pharmacokinetic characteristics had also been reported for other monoclonal antibody drugs. Bevacizumab is a humanized monoclonal antibody approved for solid tumors, including colorectal, that targets vascular endothelial growth factor A (VEGF-A). Pharmacokinetics studies performed on a patient with renal cell carcinoma who was undergoing hemodialysis at the time of treatment found the area under the curve (AUC) to be half of that of patients with normal renal function (45 205 vs. 97 488). However, this patient was receiving half of the usual dose (5 mg/kg/14 days). Pre- and post-dialysis levels also suggest no removal by hemodialysis [14]. Similar experience is also reported with eculizumab, which is a humanized monoclonal antibody that targets C5 and inhibits terminal complement activation. During the maintenance phase of treatment of a patient with end stage renal disease and paroxysmal nocturnal hemoglobinuria, pharmacokinetics studies found that 900 mg every 14 days produced therapeutic levels. No eculizumab was detected in the dialysate [15].

With regard to the radioimmunoconjugate Zevalin, information is available on the dose of radiation absorbed by the kidney as measured by ¹¹¹indium (¹¹¹In) ibritumomab tiuxetan imaging and dosimetry. Pharmacokinetics studies from four phase I, II and III trials that included patients with serum creatinine < 2.0 mg/dL showed that the median dose of radiation absorbed by the kidney was 0.38 Gy with a maximum of 0.61 Gy [5]. At that dose and level of renal function, no kidney injury was reported. The urinary clearance was 9.2–11.5% when measured by ¹¹¹In and 5.8% when ⁹⁰Y was directly measured. The dose absorbed, however, was nearly 10 times higher in another study, where the median dose absorbed was 2.1 (range 0.92–4.4) Gy/MBq [16]. In this study, only the left kidney was measured because of the effect of the liver on the right kidney. These values were actually more in line with a recent study that showed the absorbed dose to be 4.9 Gy/MBq, suggesting that the previous study may have underestimated the dose [17]. Despite the higher absorption, renal injury was not noted. There was evidence to suggest that the dose absorbed was related to the perfusion rate, but no correlation was made to the glomerular filtration rate [16,18].

In summary, it appears clear that when dealing with patients with relatively normal renal function, the use of rituximab and Zevalin is not nephrotoxic. This is likely because the absorbed doses of radiation are low, and the short path length of the beta radiation is not toxic to the kidney. The results of this case report [6] indicate that in the situation of renal failure the hematologic toxicity with a typical dose (0.3 mCi/kg) of Zevalin was acceptable. Pharmacokinetics studies of other monoclonal antibody drugs show no need for dosage adjustment as these drugs are not dialyzable. More cases need to be evaluated to further strengthen this statement.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.