Comparison of the effect of allopurinol and febuxostat on 2,8-dihydroxyadenine in plasma and urine: a clinical trial.

Background: Adenine phosphoribosyltransferase (APRT) deficiency is a rare, inherited metabolic disorder characterized by abundant urinary excretion of 2,8-dihydroxyadenine (DHA), causing urinary stones and chronic kidney disease. The aim of this study was to examine the effect of allopurinol and febuxostat on plasma levels and urinary excretion of DHA in individuals with APRT deficiency.

Methods: Adult individuals enrolled in the Icelandic APRT Deficiency Registry were invited to participate in a single-center, open-label, crossover, randomized clinical trial comparing the effect of allopurinol 400 mg/day and 800 mg/day and febuxostat 40 mg/day and 80 mg/day on plasma concentration and urinary excretion of DHA.

Results: Of 12 participants who initiated the study, 7 (3 females) completed the trial; median (range) age 57.7 (37.3-65.1) years. Off pharmacotherapy, the median plasma DHA was 300 (178-1315) ng/mL. In individuals taking allopurinol 400 mg/day and 800 mg/day, the median plasma DHA was 25 (below the limit of detection [LOD]-95) ng/mL and below the limit of detection (< LOD-92) ng/mL, respectively. On febuxostat 40 mg/day, the median plasma DHA was below the limit of detection (< LOD-35) ng/mL and on 80 mg/day DHA was below the limit of detection in all samples tested. The median urine DHA-to-creatinine ratio was 8.18 (6.21-18.69) mg/mmol off pharmacotherapy and 1.90 (< LOD-4.52) mg/mmol and 0.35 (< LOD-4.32) mg/mmol on allopurinol 400 mg/day and 800 mg/day, respectively. During treatment with febuxostat 40 mg/day and 80 mg/day, the urine DHA-to-creatinine ratio was 0.54 (< LOD-1.33) mg/mmol and below the limit of detection (< LOD-0.64) mg/mmol, respectively.

Conclusions: The plasma concentration and urinary excretion of DHA decreased markedly on treatment with both study drugs, although febuxostat was more efficacious than allopurinol in both prescribed doses. Trial registration number and date of registration. EudraCT No. 2021-002185-40; https://www.clinicaltrialsregister.eu/ctr-search/search?query=Research+Registry Date on which this record was first entered in the EudraCT database: 2019-03-19.