Dosage: The initial dosage of allopurinol is 50–100 mg/d. It should be titrated upward until serum uric acid is below 6 mg/ dL; this level is commonly achieved at 300–400 mg/d but is not restricted to this dose; doses as high as 800 mg/d may be needed.
As noted above, colchicine or an NSAID should be given during the first months of allopurinol therapy to prevent the gouty arthritis episodes that sometimes occur.
Febuxostat is a non-purine xanthine oxidase inhibitor that was approved by the FDA in 2009.
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Pharmacokinetics: Febuxostat is more than 80% absorbed following oral administration. With maximum concentration achieved in approximately 1 hour and a half-life of 4–18 hours, once-daily dosing is effective. Febuxostat is extensively metabolized in the liver. All of the drug and its inactive metabolites appear in the urine, although less than 5% appears as unchanged drug.
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Pharmacodynamics: Febuxostat is a potent and selective inhibitor of xanthine oxidase, thereby reducing the formation of xanthine and uric acid without affecting other enzymes in the purine or pyrimidine metabolic pathway. In clinical trials, Febuxostat at daily dosing of 80 mg or 120 mg was more effective in lowering serum urate levels than was allopurinol at a standard 300-mg daily dose. The urate-lowering effect was comparable regardless of the pathogenic cause of hyperuricemia— overproduction or underexcretion.
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Indications: Febuxostat is approved at doses of 40 or 80 mg for the treatment of chronic hyperuricemia in gout patients. Although it appeared to be more effective then allopurinol as urate-lowering therapy, the allopurinol dosing was limited to 300 mg/d, thus not reflecting the actual dosing regimens used in clinical practice. At this time, the dose equivalence of allopurinol and febuxostat is unknown.
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Adverse Effects: As with allopurinol, prophylactic treatment with colchicine or NSAIDs should be started at the beginning of therapy to avoid gout flares. The most frequent treatment-related adverse events are liver function abnormalities, diarrhea, headache, and nausea. Febuxostat is well tolerated in patients with a history of allopurinol intolerance. There does not appear to be an increased risk of cardiovascular events.
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Dosage: The recommended starting dose of febuxostat is 40 mg daily. Because there was concern for cardiovascular events in the original phase 3 trials, the FDA approved only 40-mg and 80-mg dosing. No dose adjustment is necessary for patients with renal impairment since it is highly metabolized into an inactive metabolite by the liver.
Pegloticase is the newest urate-lowering therapy to be approved for the treatment of refractory chronic gout.
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Chemistry: Pegloticase is a recombinant mammalian uricase that is covalently attached to methoxy polyethylene glycol (mPEG) to prolong the circulating half-life and diminish immunogenic response.
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Pharmacokinetics and Dosage: The recommended dose for pegloticase is 8 mg every 2 weeks administered as an intravenous infusion. It is a rapidly acting drug, achieving a peak decline in uric acid level within 24–72 hours. The serum half-life ranges from 6 to 14 days. Several studies have shown earlier clearance of PEG-uricase (mean of 11 days) due to antibody response when compared to PEG-uricase antibody-negative subjects (mean of 16.1 days).