Reassessing the Safety Profile of Lesinurad in Combination with Xanthine Oxidase Inhibitor Therapy.

INTRODUCTION: The rate of adverse renal events has been shown to be higher in patients treated with lesinurad plus a xanthine-oxidase inhibitor (XOI) than in patients treated only with a XOI. We reassessed the risks for various adverse renal events from a different perspective and devised a hypothesis to explain the results.

METHODS: We used data from phase 3 trials that were publicly available from the full prescribing information document and estimated the relative risk and the number needed to treat for increased serum creatinine (sCri), renal failure, and renal lithiasis. We examined these risks for each treatment group and the risks stratified by estimated glomerular filtration rate (eGFR).

RESULTS: Overall, the relative risk for sCri was > 1.0 with the 400 mg/day dose of lesinurad and higher with the 200 mg/day dose, but it was < 1.0 for both lithiasis and renal failure with the 200 mg/day dose. The relative risk was only statistically significant for sCri with the highest dose of lesinurad. When results stratified by eGFR were considered, the rates of adverse events increased with declining renal function, but the relative risks decreased in parallel, as the rate of adverse events increased much more in the placebo arm than in the active arm (200 mg/day dose). Indeed, the relative risk was only significant for the highest dose of lesinurad in patients with normal eGFR.

CONCLUSION: The rate of sCri events was higher in patients treated with both lesinurad and a XOI rather than a XOI alone. This rate was found to increase with decreasing eGFR, but as it does in for both active and placebo arms the relative risk is not different from that observed in the placebo arms in the labeled 200 mg/day dose. This may be explained by pathophysiological changes that develop in chronic kidney disease.