Pharmacokinetics and Pharmacodynamics

Rasburicase is tetramer composed of four monomeric subunits, each with a molecular mass of 34 kDa. It has a half-life of 16 to 21 hours following intravenous administration at doses of 0.15 mg/kg and 0.2 mg/kg. There is no evidence of drug accumulation in children after steady-state levels are achieved at 48 to 72 hours, but there are few data on the pharmacokinetics of rasburicase in adults and the elderly. Clearance of enzyme, by peptide hydrolysis, is not, however, influenced by renal or hepatic function and rasburicase has no effect on cytochrome P450 activity. The licensed recommendation for dosing for the prevention or treatment of tumor lysis is 0.15 to 0.2 mg/kg once daily in 50 ml of normal saline as an intravenous infusion over 30 minutes for 5 days, but there is much data to suggest that lower doses, and single doses, can be used to control hyperuricemia in adults as well as children following tumor lysis.

Efficacy of Rasburicase in Preventing and Treating Tumor Lysis Syndrome

In an open-label phase I/II study of the efficacy and safety of rasburicase in 131 patients, 20 years old or younger, receiving chemotherapy for acute lymphoblastic leukemia or advanced non-Hodgkin lymphoma, treatment with rasburicase 0.2 mg/kg every 12 hours for 48 hours was followed by reduction of plasma urate levels from 9.7 mg/dL to 1.0 mg/dL in 65 children who were hyperuricemic and from 4.3 mg/dL to 0.5 mg/dL in 66 children who did not have raised plasma urate levels before therapy ( p = .0001). None of the patients required dialysis and none developed tumor lysis syndrome. In a single nonblinded randomized controlled comparison of treatment with rasburicase or allopurinol in 52 pediatric patients with lymphoma or leukemia receiving chemotherapy, the frequency of normalization of serum urate was significantly greater in hyperuricemic patients receiving rasburicase (risk ratio [RR] 19.09, 95% confidence interval [CI] 1.28 to 285.41) and the area under the curve of serum urate at 96 hours was significantly lower in the rasburicase group (MD-201, 95% CI –258.05 to –143.95). However, a recent Cochrane systematic review of trials of nonrecombinant and recombinant urate oxidase for the treatment and prevention of tumor lysis syndrome in children with cancer concluded that while it was effective in reducing the serum urate, there was currently no conclusive evidence that it was effective in reducing renal failure or mortality from tumor lysis syndrome in children with malignancies.

Efficacy of Rasburicase in Primary Purine Overproducers

There is a single case report recording the safety and efficacy of intravenous rasburicase (0.2 mg/kg/day for 3 days) in preserving renal function in a 26-day-old boy with Lesch-Nyhan syndrome presenting with renal insufficiency, metabolic acidosis, hyperuricemia, and hyperuricosuria associated with overproduction of uric acid and severe deficiency of hypoxanthine-guanine phosphoribosyl transferase.

Use of Rasburicase for the Treatment of Gout

Although no controlled trials of rasburicase for the treatment of gout have been undertaken, and rasburicase is not licensed or approved for treating gout anywhere in the world, it has been used to treat a small number of difficult cases, where other approaches to lowering urate levels had failed or were inappropriate.

In 2000, Phillips et al. reported regression of tophi following treatment with rasburicase in a patient with end-stage renal disease and severe tophaceous gout that was resistant to allopurinol.

In 2005, Vogt documented successful treatment of a 33-year-old woman with severe progressive tophaceous gout, allopurinol hypersensitivity, and chronic renal insufficiency following transplantation for end-stage renal failure. Serum urate decreased from baseline levels of about 850 μmol/L to less than 50 μmol/L a few days after commencing rasburicase 0.15 mg/kg IV but then returned to baseline despite continuing therapy with infusions every second week for 6 months. However, gout flares gradually ceased, tophi diminished in size, and the recombinant uricase was well tolerated with continuing infusions of rasburicase fortnightly, and subsequently monthly, over 3 years. The prolonged efficacy and tolerance of repeated infusions of rasburicase over such a long period in this patient may have been in part attributable to the co-administration of immunosuppressive treatment with cyclosporine A and prednisolone.

Moolenburgh et al. reported on a 57-year-old man with primary gout who had progressive tophaceous disease, recurrent flares, and persistent hyperuricemia despite combination therapy with allopurinol 900 mg and benzbromarone 200 mg/day. Hyperuricemia persisted in the range 0.45 to 0.55 mmol/L even after further escalation of the allopurinol dose to 1800 mg/day. Treatment with rasburicase 0.2 mg/kg IV over 60 minutes daily for 1 week resulted in an immediate fall in serum urate to less than 0.01 mmol/L. Continuing treatment with weekly infusions of rasburicase was initially associated with serum urate levels that sometimes rose again to more than 0.6 mmol/L immediately before the next infusion, as well as with regular postinfusion flares of gout requiring intravenous dexamethasone for symptom control. These ceased, however, after 3 months of therapy when serum urate levels were consistently in the normal range. Decreasing the frequency of the rasburicase infusions from 1 to 2 weeks was followed by a rise in serum urate to greater than 0.6 mmol/L and a recurrence of gout attacks, but subsequent maintenance treatment with weekly infusions of rasburicase (0.2 mg/kg) was followed by gradual cessation of gout flares, stabilization of the serum urate in the range 0.25 to 0.27 mmol/L and measurable decrease in the size of tophi ( Fig. 14-3 ).

Reduction in the size of tophi in a patient with gout following 12 months treatment with rasburicase (0.2 mg/kg weekly).

(From Moolenburgh JD, Reinders MK, Jansen TLThA. Rasburicase treatment in severe tophaceous gout: a novel therapeutic option. Clin Rheumatol 2006;25:749-52.)

One small retrospective study in 10 patients with tophaceous gout, that could not be treated with allopurinol, compared outcomes and short-term safety in five patients who had received IV infusions of rasburicase 0.2 mg/kg daily for 5 days with five patients treated with 6 consecutive monthly infusions of raburicase. Patients in both groups were given 60 mg dexamethasone to prevent gout flares. In the first group a rapid and profound fall in the serum urate immediately following infusion was not sustained at 1 month (511.5 ± 128.4 μmol/L) or 2 months (572 ± 96.2 μmol/L) compared with the baseline serum urate of 573.6 ± 48.2 μmol/L. Infusions were followed by gout flares and there was no noticeable change in the size of tophi. In those given monthly treatment, the serum urate fell significantly from 612.6 ± 162.4 μmol/L at baseline to 341.2 ±91.8 μmol/L ( p = .001) after six infusions, and reduction in the size of tophi was observed in two patients. However, one patient developed bronchospasm and one developed urticaria during the sixth infusion. Two others from this group, who continued with monthly injections of rasburicase, had to discontinue therapy after 8 months because of cutaneous allergic reactions, and one patient developed a new tophus, as well as hyperuricemia that was refractory to further rasburicase after 14 monthly infusions; presumably because of the development of neutralizing antibodies.

Wider use of rasburicase as a debulking agent in patients with tophaceous gout or for the long-term management of patients with gout that cannot be treated with other urate-lowering drugs is limited by its short half-life, the development of neutralizing antibodies, significant risk of immune-mediated serious side effects, and with loss of efficacy after 6 to 15 months of therapy.

Immunogenicity and Adverse Effects Associated With Non-PEGylated Uricases

Most of the information about the immunogenicity and adverse effects associated with the administration of non-PEGylated, nonrecombinant, and recombinant A. flavus urate oxidase comes from trials and clinical experience in children and young adults with malignancy-associated hyperuricemia.

Rasburicase was remarkably well tolerated in both children and adults in the North American multicenter, compassionate use trial with a low (6%) incidence of adverse events. Only 10 of 1069 patients (less than 1%) were withdrawn as a result of events that might be drug related. During the first course of treatment, 12 patients (1.1%) had hypersensitivity reactions (pruritis, urticaria, bronchospasm, or edema) and one had an anaphylactic reaction. Antibodies to rasburicase were detected in 13% of patients after a single infusion. However, the incidence of hypersensitivity reactions in patients treated with rasburicase is much lower after both single and repeated infusions than in patients treated with nonrecombinant uricase, presumably because of greater purity of the recombinant protein and possibly because of increased immunogenicity associated with modification of an active cysteine during the extraction and purification of Uricozyme.

Side Effects Associated With the Generation of Hydrogen Peroxide

Among the more serious adverse events that followed treatment with rasburicase that were not attributable to hypersensitivity were four cases of hemolytic anemia and three patients with methemoglobinemia. In one of the patients who developed hemolysis, glucose-6-phosphate dehydrogenase (G6PD) deficiency was subsequently diagnosed. Hydrogen peroxide (H ₂ O ₂ ) is generated during uricolysis with uricase (see Fig. 14-1 ). Treatment with all urate oxidase preparations, including rasburicase, is contraindicated in patients with G6PD deficiency because of markedly increased risks of inducing hemolysis and/or methemoglobinemia. Guidelines for the management of tumor lysis syndrome in adults and children recommend screening for G6PD deficiency before treatment with rasburicase in patients with a previous history of drug-induced hemolytic anemia and in patients from certain ethnic groups in which G6PD deficiency occurs more frequently (African, Mediterranean, and Southeast Asian ancestry). Patients should be monitored for evidence of cyanosis during uricase infusions and full blood counts should be undertaken during and after treatment.

It is also important to monitor plasma urate levels regularly. Blood should be collected in prechilled heparinized tubes and plasma urate assayed at 4°C within 4 hours of collection, to avoid spuriously low measurements of serum urate, as a result of urate degradation in vitro by uricase activity in serum at room temperature.