Pharmacokinetics of Intravenous Uricase-PEG 20, a Drug for Managing Hyperuricemia in Tumor Lysis Syndrome.

Tumor lysis syndrome can result in hyperuricemia and the precipitation of monosodium urate crystals in the renal tubules, leading to renal failure and dialysis. The enzyme uricase, found in most mammals but not humans, metabolizes uric acid into the highly soluble allantoin. Rasburicase (Elitek/Fasturtec, Sanofi Aventis), an unmodified recombinant uricase, is used to treat and prevent hyperuricemia associated with tumor lysis syndrome. However, it requires multiple doses and is highly immunogenic. Uricase-PEG 20 is a pegylated recombinant uricase, designed to have an extended half life and reduced immunogenicity compared with unmodified uricase, that has been administered intramuscularly to gout patients in clinical studies. However, it has not previously been studied as an intravenous agent.

Intravenous toxicology studies, including pharmacokinetic studies, were performed with Uricase-PEG 20 in rats and cynomolgus monkeys. Uricase-PEG 20 was administered to rats at 1, 4 and 10 mg/kg and uricase enzyme activity was assessed at 1, 6, 24, 72 and 144 hrs after dosing. In monkeys, Uricase-PEG 20 was administered at 0.5, 1 and 5 mg/kg and uricase activity was assessed at 15 min and 1, 4, 24, 72 and 144 hrs after administration.

In rats, the half-life for Uricase-PEG 20 ranged from 44.2 to 104.5 hrs (median, 70.7 hrs); the volume of distribution varied from 38.8 to 129.0 mL/kg (median 94.6), and the clearance varied from 0.70 to 1.48 mL/hr/kg. In monkeys, the half-life ranged from 184 to 214 hrs (median 194.5 hrs), the volume of distribution ranged from 17.2 to 25.2 mL/kg (median 19.9 mL/kg), and the clearance ranged from 0.063 to 0.102 mL/hr/kg. In both species, measures of exposure including C_max and AUC_last increased in a dose-proportional manner. The median half-lives of 70.7 hrs in rats and 194.5 hrs in cynomolgus monkeys is significantly longer than the half-life reported for rasburicase in similar models (<2 hrs in rats and <4 hrs in baboon monkeys).

The long half-life of Uricase-PEG 20 compared to that of unmodified uricase suggests that Uricase-PEG 20 may require less frequent dosing and thus have better clinical utility than unmodified uricase. Uricase-PEG20 will be used at intravenous doses ranging from 0.05 to 0.4 mg/kg in initial human studies.

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