Achieving Target Urate in Gout: How Much Allopurinol Is Needed?

According to trial data published in Arthritis Research & Therapy, baseline serum urate, creatinine clearance (CrCL), weight, and allopurinol dose may be predictive of the allopurinol dose necessary to achieve target serum urate level among patients with gout.

Investigators designed a 24-month parallel-group, randomized controlled trial in which patients with gout were assigned to either continue current allopurinol dose for 12 months and then enter a dose-escalation phase or to begin allopurinol dose escalation immediately. During dose escalation, allopurinol was increased monthly until serum urate was <6 mg/dL. Allopurinol dose was increased in 50-mg and 100-mg increments for those with CrCL ≤60 mL/min and CrCL >60 mL/min, respectively. Data obtained during the 12-month dose-escalation phase of the study were combined for analysis. Recommended CrCL-based dose (R+) was defined as the number of milligrams of allopurinol above baseline CrCL-based dose participants had achieved by the end of dose escalation. R+ was stratified into the following 3 groups: R+ ≤100 mg/d, R+ 101 to 200 mg/d, and R+ ≥201 mg/d. The primary efficacy outcome was mean serum urate level at the conclusion of the dose-escalation phase. Multiple linear regression analysis was performed to assess the associations of baseline clinical features and allopurinol dose at 12 months.

Among the 132 participants who completed the 12-month dose-escalation phase, the R+ dose of allopurinol at the final visit was ≤100 mg/d in 28.8% of participants, 101 to 200 mg/d in 34.8% of participants, and ≥201 mg/d in 37.1% of participants. Among those with R+ ≥201 mg/day, great range in dosage was observed, with a maximum observed value of 700 mg/d. Those who required R+ dose >200 mg/d were significantly younger, had higher baseline serum urate levels, were more likely to be obese (body mass index ≥ 30 kg/m²), and were receiving more allopurinol at the start of the dose-escalation phase. Multivariate analysis confirmed that baseline CrCL, baseline serum urate level, weight, and baseline allopurinol dose were all significantly positively associated with allopurinol dose at 12 months (all P <.01). However, there was no significant difference among the 3 R+ groups in the number of participants achieving target serum urate level, although increasing R+ was associated with an increase in plasma oxypurinol and a greater change in serum urate levels. Numerically, there were more patients with severe adverse events in the higher R+ group than in the lower R+ groups, although this was not statistically significant. None of the severe adverse events were thought to be allopurinol related, although further research is necessary to affirm this conclusion.

A large range of allopurinol doses is necessary to achieve target serum urate level, and baseline clinical features may be helpful in predicting the optimal dosing for patients. The relationship between R+ and serious adverse events requires further investigation.

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Reference

Stamp LK, Chapman PT, Barclay ML, et al. How much allopurinol does it take to get to target urate? Comparison of actual dose with creatinine clearance-based dose. Arthritis Res Ther. 2018;20:255.