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.
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.