Rasburicase

In humans, uric acid is the final step in the catabolic pathway of purines. The acute increase in plasma levels of uric acid subsequent to the lysis of large numbers of malignant cells and during cytoreductive chemotherapy may lead to impairment of renal function and renal failure resulting from the precipitation of crystals of uric acid in renal tubules. Rasburicase is a highly potent uricolytic agent that catalyses enzymatic oxidation of uric acid into allantoin, a water soluble product, easily excreted by the kidneys in the urine.

The enzymatic oxidation of uric acid leads to stoichiometric formation of hydrogen peroxide. The increased of hydrogen peroxide over ambient levels can be eliminated by endogenous antioxidants and the only increased risk is for haemolysis in G6PD deficient and inherited anaemia patients.

In healthy volunteers, a marked dose-related decrease in plasma uric acid levels was observed across the dose range 0.05 mg/kg to 0.20 mg/kg of rasburicase.

The pharmacokinetics of rasburicase were evaluated in both paediatric and adult patients with leukaemia, lymphoma or other haematological malignancies.

Absorption

After infusion of rasburicase at a dose of 0.20 mg/kg/day, steady state is achieved at day 2-3. Minimal accumulation of rasburicase (<1.3 fold) was observed between days 1 and 5 of dosing.

Distribution

The mean volume of distribution ranged from 110-127 ml/kg in paediatric patients and from 75.8 to 138 ml/kg in adult patients, respectively, which is comparable to the physiological vascular volume.

Metabolism

Rasburicase is a protein, and therefore: 1) not expected to bind to proteins, 2) expected that metabolic degradation will follow the pathways of other proteins, i.e. peptide hydrolysis, 3) unlikely to be candidate for drug-drug interactions.

Elimination

Clearance of rasburicase was ca. 3.5 ml/h/kg. The mean terminal half-life was similar between paediatric and adult patients and ranged from 15.7 to 22.5 hours. Clearance is increased (ca. 35%) in children and adolescents compared to adults, resulting in a lower systemic exposure. Renal elimination of rasburicase is considered to be a minor pathway for rasburicase clearance.

Special patient populations

In adults (≥ the age of 18 years), age, gender, baseline liver enzymes and creatinine clearance did not impact the pharmacokinetics of rasburicase. A cross-study comparison revealed that after administration of rasburicase at 0.15 or 0.20 mg/kg, the geometric mean values of body-weight normalized clearance were approximately 40% lower in Japanese (n=20) than that in Caucasians (n=26).

As metabolism is expected to occur by peptide hydrolysis, an impaired liver function is not expected to affect the pharmacokinetics.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. The interpretation of the non-clinical studies is hampered due to the presence of endogenous urate oxidase in standard animal models.