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Abstract: PO2025

Association of Oxypurinol Exposure with Progression of CKD: Pre-Specified Substudy Results from the CKD-FIX Trial

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Tiku, Anushree, The George Institute for Global Health, Newtown, New South Wales, Australia
  • Wright, Daniel, University of Otago, Dunedin, New Zealand
  • Day, Richard O., University of New South Wales, Sydney, New South Wales, Australia
  • Stocker, Sophie, The University of Sydney, Sydney, New South Wales, Australia

Group or Team Name

  • CKD-FIX Study Group Trial Steering Committee
Background

The CKD-FIX trial evaluated the effect of allopurinol on eGFR slope over 104 weeks in patients with chronic kidney disease (CKD) and risk of progression. The aim of this pre-specified substudy was to assess whether exposure to oxypurinol, the active metabolite of allopurinol, predicts change in eGFR.

Methods

Adults with CKD stage 3 or 4 (n=369), no history of gout, and high risk of progression (urinary albumin-to-creatinine ratio ≥265 mg/g or eGFR decrease ≥3.0 mL/min/1.73 m2 in the preceding year) were randomized to receive allopurinol (n=185) or placebo (n=184). Plasma oxypurinol concentrations were determined at weeks 16, 24, 40, 56, 72, 88 and 104 post-initiation of allopurinol. Non-compartmental pharmacokinetic analysis of oxypurinol concentrations was performed to determine oxypurinol exposure (area under the concentration time curve) using the SimBiology module of MATLAB. The association between eGFR slope and oxypurinol exposure was assessed using least-squares estimates linear regression.

Results

Overall 155 (84%) patients (mean eGFR 31.7 mL/min/1.73 m2, mean serum urate 8.0 mg/dL) received allopurinol and had ≥1 plasma oxypurinol concentration available. At the end of the 12-week dose-escalation phase, the majority of patents (123; 79%) were prescribed allopurinol 300 mg and the remainder 100 mg (13; 8%) or 200 mg (19; 12%). The mean (standard deviation) eGFR slope and reduction in serum urate concentration were -3.32 (5.02) mL/min/1.73 m2/year and 2.6 (0.14) mg/dL, respectively. Based on a total of 819 plasma oxypurinol concentrations (median n=6 per patient), there was no correlation between eGFR slope and total oxypurinol exposure (P=0.93), including after adjusting for allopurinol dose (P=0.99). These results were consistent across the three allopurinol dosing regimens. Greater oxypurinol exposure was associated with larger reduction in serum urate concentrations (P<0.0001).

Conclusion

In CKD-FIX participants, exposure to oxypurinol was not associated with change in eGFR. However, reduction in serum urate concentration was dependent on plasma oxypurinol exposure.

Funding

  • Private Foundation Support