Abstract
ObjectiveAllopurinol dosing has frequently been limited based on creatinine clearance (CrCL), resulting in failure to achieve target serum urate (SU). The aim of this analysis was to determine how many milligrams of allopurinol above the recommended CrCL-based dose (R+) are required to achieve target SU and to investigate the factors that influence R+.MethodsWe analysed data from participants in a 24-month open, randomized, controlled, parallel-group, comparative clinical trial. Data obtained during the 12-month dose escalation (DE) phase of the study (year 1 for DE/DE and year 2 for control/DE) were combined. R+ dose was defined as the number of milligrams of allopurinol above the CrCL-based dose at the final visit.ResultsOf the 132 participants, R+ allopurinol dose at the final visit was ≤ 100 mg/day in 38 (28.8%), 101–200 mg/day in 46 (34.8%) and > 200 mg/day in 48 participants (37.1%). There was no significant difference between the R+ groups in the number of participants achieving target SU. There was an increase in plasma oxypurinol and a larger percentage and absolute change in SU as R+ increased. Multivariate analysis revealed CrCL, weight, baseline SU and allopurinol dose, were significantly positively associated with allopurinol dose at 12 months. There were no significant differences across R+ groups in renal or liver function adverse events, although there were numerically more serious adverse events in the higher R+ groups.ConclusionA wide range of R+ doses are required to achieve target SU. Four easily obtained clinical variables (baseline SU, CrCL, weight, and allopurinol dose) may be helpful to predict allopurinol dose.Trial registrationANZCTR, ACTRN12611000845932. Registered on 10 August 2011.
Highlights
Allopurinol remains the most commonly used urate-lowering therapy
R+ allopurinol dose was defined as the number of milligrams of allopurinol above baseline CrCL-based dose, and participants were grouped according to the allopurinol dose at the final visit of the dose escalation phase into one of the following three groups: R+ ≤ 100 mg/day, R+ 101–200 mg/day, R+ ≥ 201 mg/day
Serum urate There was no significant difference between the three R+ groups in the number of participants achieving target serum urate: ≤ 100 mg/day, 27/38 (71.1%); 101–200 mg/day, 38/46 (82.6%) and > 200 mg/day, 37/48 (77.1%); p = 0.45 (Table 2)
Summary
Allopurinol remains the most commonly used urate-lowering therapy. Many clinicians have adhered to the creatinine-clearance (CrCL) based dosing recommendation published in 1984 by Hande et al [1] believing that this will reduce the risk of the potentially fatal allopurinol hypersensitivity syndrome (AHS). While higher starting doses of allopurinol have been associated with AHS [2] there is little evidence that the. The aims of this pre-specified secondary analysis were to determine how much above CrCL-based allopurinol dose study participants required to achieve target SU, Stamp et al Arthritis Research & Therapy (2018) 20:255 factors that influence the R+ requirement and identify any safety signal with higher R+ requirement
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