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phosphate precipitation. ARF is the most feared immediate complication of hematological malignancies, as it requires dialysis and has a negative impact on the outcomes of patients with malignancies [22-31].

8.3.2 Medical Conditions Requiring Uricolytic Therapy

Gout, a chronic disease, is controlled by uricosuric agents which enhance the renal excretion of uric acid, or by xanthine oxidase inhibitors such as allopurinol. Uricolytic therapy is not the treatment of choice for gout, as it requires continuous treatment rather than a decrease in plasma uric acid concentration within a few hours. In contrast, since ARF, a consequence of acute hyperuricemia, is a life-threatening condition, any acute increase in uric acid plasma concentration has to be urgently treated or, ideally, prevented. Uricolytic therapy, through its fast-acting and highly effective action, fully meets these requirements.

8.3.2.1 Physiopathology

Malignant cells contain more nucleic acid than normal cells, and have a much higher cellular turnover. Although malignancies with high tumor burden and high proliferative rate may lead to spontaneous hyperuricemia, chemotherapy more readily induces TLS, since malignant cells are sensitive to treatment. These patients, even those who present with normal plasma uric acid concentrations, are metabolically unstable and at risk of metabolic perturbations triggered by dehydration and chemotherapy-induced tumor lysis. Thus, chemotherapy can be initiated only in metabolically stable patients with controlled plasma uric acid concentrations, and uricolytic therapy must be initiated prior to starting cytoreductive therapy in patients with or at risk of TLS.

8.3.2.2 Diseases and Causes of Acute Hyperuricemia

Diseases with high tumor burden or high tumor cell proliferation rate and tumors with high sensitivity to cytotoxic drugs present the highest risk of TLS and, therefore, hyperuri-cemia. These diseases are myeloproliferative diseases and hemopoietic tumors occurring in children and adults. Among myeloproliferative diseases and hemopoietic tumors, acute lymphoblastic leukemia, acute myeloid leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, blastic crises of chronic myeloid leukemia, and non-Hodgkin's lymphoma are the most frequently associated with TLS. Plasma cell disorders, such as multiple myeloma and myelodysplastic syndrome, may be responsible for TLS as well. Among lymphomas and leukemias, advanced-stage Burkitt's lymphoma and B-cell acute lymphoblastic leukemia, high-proliferative-rate diseases, are at the highest risk for severe TLS and subsequent renal failure [32]. Solid tumors have been reported to induce TLS, among which are germ cell tumors and small-cell lung cancer. White blood cell count and lactate dehydrogenase are parameters of tumor load. Elevated plasma levels are good indicators of high risk of TLS [29,31].

Treatment must be started prior to initiation of cytotoxic therapy, to control plasma uric acid concentration and avoid renal complications. This treatment must be fast-acting to avoid any delay in chemotherapy initiation in potentially curable patients at risk of threatening symptoms associated with a high tumor burden and high proliferation rate, such as hyperleukocytosis and hyperviscosity syndrome.

Gout is a disease characterised by chronic hyperuricemia and a mild plasma uric acid concentration increase, and therefore does not represent an indication to be treated by rasburicase. Nevertheless, a few patients with allopurinolallergy, and allograft transplant recipients were successfully treated by rasburicase [33,34].

8.4 Developmental History of the Enzyme 8.4.1 Rasburicase

Urate oxidase is present in most mammals, but primates and humans have lost this enzyme owing to genetic mutations that took place during the evolutionary process. The pharmacokinetics of rasburicase following a 30 min intravenous (IV) infusion is linear over the dose range of 0.05 to 0.20 mg/kg. Rasburicase is a protein enzyme with a low clearance rate (2.3 to 3.8 mL/h/kg) and has a mean volume of distribution similar to the vascular space. The mean elimination half-life is approximately 18 h and is independent of the dose administered. There is no significant correlation between hepatic function and uricolytic activity, and the renal elimination of rasburicase is a minor pathway for rasbu-ricase clearance. There is no need for dose adjustments with respect to the regarding gender and age of the patients, provided that rasburicase is dosed in a mg/kg manner. Like other proteins, rasburicase is expected to be hydrolyzed with reincorporation of amino acids into new cellular proteins. No drug-drug interactions were observed from preclinical studies or reported from clinical use.

Rasburicase is active at the end of the purine catabolic pathway. The recommended dose of rasburicase is 0.15 or 0.20 mg/kg/d, administered once daily. The median treatment duration is 3 to 5 d [21,29,39].

8.4.1.1 Mechanism of Action

Rasburicase is a recombinant urate oxidase enzyme that catalyzes the enzymatic oxidation of uric acid into allantoin, as shown in Figure 8.1. In contrast to uric acid, allantoin is readily water-soluble, facilitating its elimination by urinary excretion. The reactive by-product of this reaction, hydrogen peroxide, is then neutralized by catalase to form oxygen and water.

8.4.2 Safety of Rasburicase

Rasburicase is well tolerated. The most important safety concern is allergic reactions, such as anaphylaxis, which may occur because rasburicase is an heterologous protein. Allergic reactions tend to occur within 10 min after beginning infusion of the first dose. The incidence of hypersensitivity reactions is 1% [29,35,40], while the incidence of severe allergic reactions is 0.5% [29] or less [31,36,37].

Rasburicase may induce hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency because hydrogen peroxide, an oxidizing agent, is one of the major by-products of the conversion of uric acid into allantoin. Hemolysis and methemoglobinemia have been reported in patients with an incidence of 0.5% [38] or less [36]. It is not known whether patients with deficiency of methemoglobine reductase are at increased risk for methemoglobinemia or hemolytic anemia.

Other adverse events have been recorded during treatment with rasburicase but the relationship to rasburicase was not known as the adverse events might also have been related to the underlying disease state and its treatment with cytotoxic chemotherapy. The most frequent adverse events reported were headache, nausea, fever, and vomiting, with an incidence of about 5%.

Rasburicase should not be administered to patients with a known history of anaphylactic reactions or known history of hypersensitivity reactions to rasburicase or any of the excipients. Rasburicase is contraindicated in patients with known G6PD deficiency.

8.4.3 Results of Rasburicase Treatment

Rasburicase has been successfully used in patients with myeloproliferative diseases and hemopoietic tumors, leading to hyperuricemia or at risk of TLS.

Rasburicase efficacy is assessed by plasma uric acid concentration measurements. Caution has to be taken to ensure accurate uric acid measurements. Rasburicase will cause enzymatic degradation of the uric acid within blood samples left at room temperature, resulting in spuriously low uric acid levels. Blood must be collected in prechilled tubes containing heparin anticoagulant and immediately immersed and maintained in an ice water bath. Plasma samples must be assayed within 4 h of sample collection.

Rasburicase produces rapid and pronounced reduction in plasma uric acid concentrations in patients, regardless of whether they are hyperuricemic at baseline [21,29,31,36,39,41,42-44]. Mean plasma uric acid concentration is reduced by more than 80% 4 h after the first dose of rasburicase in patients. Rasburicase effectively prevents secondary increases of uric acid concentration >8 mg/dL in most of the patients, and plasma uric acid remains controlled 24 h after the last dose of rasburicase, as shown in Figure 8.5.

(N=107) (N=103) (N=101) (N=95) (N=98) (N=47) (N=36) (N=1) (N=105)

Time from first dose (h)

FIGURE 8.5 Plasma uric acid concentration after the first dose of rasburicase.

(N=107) (N=103) (N=101) (N=95) (N=98) (N=47) (N=36) (N=1) (N=105)

Time from first dose (h)

FIGURE 8.5 Plasma uric acid concentration after the first dose of rasburicase.

Through its rapid onset of action, rasburicase enables the initiation of chemotherapy treatment in a timely manner and without delay, which constitutes a critical issue in the treatment of proliferative diseases [40,45,46].

An improvement in renal function has been observed in patients with baseline-elevated serum creatinine. In these patients, serum creatinine levels dropped within a few days (Figure 8.6).

The frequency of ARF was significantly decreased when rasburicase was used in the management of TLS [21,29,31,36,39-43,47]. It has been clearly established that maintenance of renal function is a factor of great importance in the management of these patients who receive chemotherapy and who therefore require dose adjustments to minimize toxicity. Furthermore, these patients are candidates for potentially curative chemotherapy and at risk for late complications from the treatment of their original malignancy. In this context, early preservation of renal function appears highly desirable.

Rasburicase has been commercially available since 2002. Rasburicase is indicated for:

1. The treatment of hyperuricemia due to rapid tumor lysis in pediatric and adult patients

2. The prevention of chemotherapy-induced hyperuricemia in pediatric and adult patients who have malignancies associated with rapid tumor lysis

Compared with previous treatments of TLS, i.e., hydration alkalinization and allopurinol therapy, rasburicase reduces uric acid levels more rapidly and more effectively, and improves renal function with a good safety profile. Rasburicase used to prevent and treat

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