Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout

Abstract

Objective. To evaluate the efficacy, immunogenicity, and tolerability of intravenous (IV) PEGylated recombinant mammalian urate oxidase (PEG-uricase) for the treatment of severe gout.Methods. Single infusions of PEG-uricase (at doses ranging from 0.5 mg to 12 mg) were administered to 24 patients (6 cohorts of 4 patients each) in a phase I clinical trial. Plasma uricase activity (pUox), the plasma urate concentration (pUAc), and the uric acidto-creatinine ratio (UAc:Cr) in urine were monitored for 21 days after dosing. Adverse events and the IgG antibody response to PEG-uricase were followed up for 35 days.Results. All patients completed the trial. Maximum pUox was linearly related to the IV dose of PEG-uricase, the area under the curve (AUC) value increased linearly (up to a dose of 8 mg), and the pUox half-life was 6.4-13.8 days. After doses of 4-12 mg, the pUAc fell within 24-72 hours, from a mean ؎ SD value of 11.1 ؎ 0.6 mg/dl to 1.0 ؎ 0.5 mg/dl; the AUC value for the pUAc was equivalent to maintaining the pUAc at 1.2-4.7 mg/dl for 21 days postinfusion. The UAc:Cr ratio in urine fell in parallel with the pUAc. IgG antibodies to PEG-uricase, mostly IgG2 and specific for PEG, developed in 9 patients, who had more rapid enzyme clearance but no allergic reactions. All adverse events were mild to moderate, with gout flares being most common.Conclusion. The bioavailability, efficacy, and tolerability of IV PEG-uricase were greater than the bioavailability, efficacy, and tolerability observed in a previous phase I trial of subcutaneous PEG-uricase. Infusing 4-12 mg of PEG-uricase every 2-4 weeks should maintain the pUAc well below the therapeutic target of 6 mg/dl and greatly reduce renal uric acid excretion. This treatment could be effective in depleting expanded tissue urate stores in patients with chronic or tophaceous gout.

Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo

“…Speculation that pegloticase therapy may increase H 2 O 2 to toxic levels (25) implies a greater rate of production than elimination. Before clinical testing we considered this possibility unlikely for these reasons: (i) because of PEGylation, infused pegloticase would be restricted to plasma (20); (ii) H 2 O 2 freely crosses cell membranes; and (iii) erythrocytes are known to have a prodigious capacity to decompose H 2 O 2 generated within the vascular compartment (26,27). We estimate that erythrocytes can eliminate H 2 O 2 2-3 orders of magnitude faster than it can be produced by pegloticase therapy (Table 1).…”

“…The importance of this rate disparity is evident in studies performed with the CEM human T-cell leukemia line ( Fig. 1), in which culture medium was supplemented with 0.3 or 0.5 mM urate and 40 mU/mL of pegloticase, close to the maximal plasma activity during therapy (20), and able to oxidize the urate in a few minutes. The combination of urate plus pegloticase, but neither alone, was highly toxic, decreasing CEM viability (Fig.…”

“…The relationship of uricase expression and PUA to oxidative stress is directly relevant to pegloticase, a PEGylated recombinant porcine uricase under investigation as an orphan drug for treating refractory gout when other therapies have failed to maintain PUA below 6 mg/dL (0.36 mM), the usual therapeutic target (19,20). In such patients, i.v.…”

Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice

“…Urate oxidase therapy is also being explored in tophaceous gout (23,26) and in patients with gout refractory to standard therapies (27,28). It has also been administered to a small number of patients after stroke (29) and in an individual with the Lesch-Nyhan syndrome (30).…”

Current and Emerging Therapies for Gout

“…In September 2010, pegloticase was approved by the FDA for the treatment of hyperuricemia in patients with gout who have failed to normalize sUA levels (G6 mg/dL) or continue to have signs and symptoms of gout on standard oral ULT [12•]. Pegloticase is an intravenously administered recombinant mammalian urate oxidase (uricase) produced from a genetically modified Escherichia coli conjugated to multiple strands of monomethoxypolyethyl glycol (PEG) [17,18]. Unlike other available ULT, pegloticase is unique in that it catalyzes the oxidation of uric acid into the more water soluble allantoin, allowing for easy excretion by the kidney [12•].…”