Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout.
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 acid-to-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.


CONCLUSIONS
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.
Sundy
John S
JS
Duke University Medical Center, Durham, North Carolina 27710, USA.
Ganson
Nancy J
NJ
Kelly
Susan J
SJ
Scarlett
Edna L
EL
Rehrig
Claudia D
CD
Huang
William
W
Hershfield
Michael S
MS
D000328:Adult; D000368:Aged; D000906:Antibodies / Q000276:immunology / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005260:Female; D006073:Gout / Q000188:drug therapy*; D006074:Gout Suppressants / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D014503:Urate Oxidase / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics*; D014527:Uric Acid / Q000652:urine
D000906:Antibodies; D006074:Gout Suppressants; D014527:Uric Acid; D011092:Polyethylene Glycols; D003404:Creatinine; D014503:Urate Oxidase; C031545:Pegloticase