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Rasburicase use outlined for treating hyperuricemia
Research should explore cost-effective dosing strategies more fully to ensure that rasburicase is used appropriately.
Tumor lysis syndrome is a metabolic complication that results from chemotherapy for malignancies that have rapid growth rates, large tumor burden and great sensitivity to the lytic effects of chemotherapy.
Leukemias and lymphomas are the most common cancers associated with tumor lysis syndrome. The rapid destruction of cancer cells dumps intracellular contents into the bloodstream faster than the body can eliminate them. These metabolic complications include hyperkalemia, hyperphosphatemia, hypocalcemia and hyperuricemia.
Tumor lysis syndrome usually starts just after starting chemotherapy and lasts for three to seven days. Tumor lysis syndrome is more common in patients with dehydration and pre-existing renal impairment. Hyperuricemia results from the oxidative metabolism of purine metabolites from nucleic acids. In this pathway, hypoxanthine is converted to xanthine, and xanthine to uric acid by an enzyme called xanthine oxidase. Since uric acid is poorly water-soluble, precipitation in the urine can occur when uric acid levels in the urine rise, causing acute renal failure in some patients.
Preserving renal function
Preventing or treating the renal impairment from hyperuricemia includes vigorous IV hydration to increase urine output and lower the uric acid concentration in the urine to help avoid precipitation. Although somewhat controversial, alkalinization of the urine (with IV sodium bicarbonate) has been used to improve the solubility of uric acid in the urine. In some severe cases, hemodialysis may be necessary. Allopurinol has long been used to prevent or treat hyperuricemia.
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Allopurinol inhibits the enzyme xanthine oxidase, and so reduces the production of uric acid. As it does not decrease the already formed uric acid, it may take two to three days for allopurinol to reduce the serum uric acid level.
Rasburicase (Elitek, Sanofi-Aventis), a fairly new medication for hyperuricemia, uses a different mechanism than allopurinol. A recombinant form of urate oxidase, this enzyme metabolizes preformed uric acid in- to allantoin, which is 10 times more water-soluble than uric acid and is easily eliminated in the urine. Rasburicase rapidly causes a profound decrease in serum uric acid levels. The traditional recommended dose is 0.15-0.2 mg/kg/day IV once daily for five days.
Cost-effective use
Unfortunately, rasburicase is extraordinarily expensive, costing more than $3,000 per day and more than $16,000 per course at the higher dose for an 80-kg adult patient. Due to the cost, clinicians often use rasburicase only in patients at the highest risk for tumor lysis syndrome, in patients with Burkitt’s lymphoma or hematologic malignancies, in patients with a high white blood cell count (WBC) of more than 50 x 109/L or in patients with a pre-chemotherapy uric acid level of more than 10 mg/dL.
Since reduction of uric acid levels to below normal values is not necessary to prevent renal impairment, more cost-effective dosing strategies for the use of rasburicase have been explored.
Using lower doses
Hummel and colleagues reported the use of lower doses of rasburicase in four adult patients with advanced lymphoma or acute leukemia with tumor lysis syndrome and renal failure. The rasburicase doses ranged from 0.017 mg/kg IV for one dose to 0.2 mg/kg/dose IV for three days. The serum uric acid levels dropped significantly in all patients and allowed the chemotherapy regimen to proceed without delay.
In another report, Lee et al administered single 4.5-mg IV doses of rasburicase to three children with high-grade lymphoma or acute leukemia. This flat dose corresponded to 0.08-0.26 mg/kg/dose. In all three patients, the pre-treatment uric acid level was more than 11mg/dL and dropped rapidly to less than 3mg/dL and remained less than the normal range when chemotherapy treatment was initiated.
Liu et al studied the use of single dose rasburicase (0.15 mg/kg IV rounded to nearest vial size) in six adults and two children. Rasburicase was restricted to patients with hyperuricemia ( > 8mg/dL), and bulky tumors (WBC > 50 x 109/L lactate dehydrogenase > 500 units/L) who required immediate chemotherapy and were at risk for tumor lysis syndrome. In all patients, the serum uric acid levels dropped rapidly and remained less than 4 mg/dL for up to four days while the chemotherapy treatments proceeded. All patients’ renal function improved to normal or to baseline.
In another report, McDonnell and colleagues administered rasburicase as a single 6-mg IV dose to 11 adult patients with hematologic malignancies who were at high risk for tumor lysis syndrome (large tumor burden, rising uric acid level).
The 6-mg IV dose corresponded to a median dose of 0.08 mg/kg (range 0.01-0.136 mg/kg). This single flat dose of rasburicase quickly and significantly lowered the uric acid level of 10 of the 11 patients from a median of 11.7 mg/dL to 2.4 mg/dL. The one nonresponding patient was obese (BMI 87) and received an adequate response after an additional 12-mg dose.
Although only a small number of patients were described in these reports, all of these investigators found that lower doses or shorter treatment courses (compared with the label-recommended regimen) of rasburicase were successful in lowering the uric acid level in a rapid and sustained manner, with subsequent resolution of renal impairment while allowing chemotherapy to proceed as planned.
Since rasburicase is an extraordinarily expensive medication, these cost-effective dosing strategies should be explored more fully to ensure that rasburicase is used appropriately.
For more information:
- Liu CY, Sims-McCallum RP, Schiffer C. A single dose of rasburicase is sufficient for the treatment of hyperuricemia in patients receiving chemotherapy. Leukemia Res. 2005;29:463-465.
- McDonnnell A, Hall PD, Lenz K, et al. A single 6 milligram dose of rasburicase for the management of tumor lysis syndrome in adults. Pharmacotherapy. 2005;25:1485.
- Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Brit J Haematol. 2004;127:3-11.
- Hummel M, Buchheidt D, Reiter S, et al. Successful treatment of hyperuricemia with low doses of recombinant urate oxidase in four patients with hematologic malignancy and tumor lysis syndrome. Leukemia. 2003;17:2542-2544.
- Lee AC, Li CH, So KT, et al. Treatment of impending tumor lysis with single-dose rasburicase. Ann Pharmacother. 2003;37:1614-1617.
About the author:
- Lisa K. Lohr, PharmD, is a clinical pharmacy specialist in oncology at Fairview University Medical Center in Minneapolis and is the section editor for pharmacology on Hem/Onc Today’s editorial board
