Background:Xanthine oxidase inhibitors (XOI) are commonly used as urate lowering therapy (ULT) for the treatment of gout. Allopurinol, the first-line treatment, demonstrates low response rate (< 40%), defined as serum urate (sUA) lowering effect below 6 mg/dL, in multiple large-scale clinical trials. As recommended in EULAR guidelines and other literatures, targeting sUA <5 mg/dL or even <4 mg/dL, provides a better opportunity to lower incidence of gout flare and resolution of tophi in gout patients. Febuxostat, a more potent XOI, has been classified as a second-line ULT agent due to increased cardiovascular risks in certain patient populations. For XOI intolerance and non-responders, replacing the agent with a potent URAT1 inhibitor or adding an URAT1 inhibitor onto a current treatment regimen provides opportunities to improve response rates in patients with refractory gout. AR882 is a uricosuric agent that blocks the reabsorption of uric acid in the apical side of renal tubule, hence increases excretion of uric acid into the urine. A phase 2a study has demonstrated the additive effects of AR882 in combination with allopurinol or febuxostat.Objectives:To evaluate the effect of AR882 alone or in combination with allopurinol or febuxostat on circulating levels and urinary excretion of hypoxanthine, xanthine and uric acid. Furthermore, to elucidate the contribution of each drug towards the combination effect in sUA lowering.Methods:Plasma, serum, and urine samples were collected from 17 patients with gout who received a once-daily dosing of AR882 50 mg, allopurinol 300 mg or febuxostat 40 mg, or in combination for one week in a phase 2a study. Samples were collected to measure hypoxanthine, xanthine and uric acid levels in plasma or serum and the amount of each excreted in the urine. Plasma Cmax and AUC and 24-hour urine excretion amount (mg) of hypoxanthine and xanthine were calculated by non-compartmental analysis method.Results:In monotherapy, AR882 demonstrated better sUA lowering effect (↓53%) compared to allopurinol (↓35%) or febuxostat (↓39%). Combination of AR882 and allopurinol lowered sUA by 66% while combination of AR882 and febuxostat lowered sUA by 71%. Based on the change of xanthine in plasma following combination treatments, it can be calculated that allopurinol contributed 28% of the urate lowering effect, whereas AR882 contributed 38% of the effect. Similarly, febuxostat contributed 33% of the urate lowering effect and AR882 contributed to about 36-38% of the effect when used in combination. The combination treatments significantly increased the response ratio for patients achieving sUA levels < 5 mg/dL, 4 mg/dL, and even 3 mg/dL. In the combination with allopurinol, 100%, 100%, 100%, and 44% patients achieved sUA < 6 mg/dL, < 5 mg/dL, 4 mg/dL, and 3 mg/dL, respectively. Similar results were seen with the combination of AR882 and febuxostat. Treatment with allopurinol or febuxostat alone resulted in 8 to 10-fold and 16-fold increases of xanthine exposure, respectively. The combination of AR882 and allopurinol or febuxostat showed approximately 5-8 fold or 13-fold increases in plasma xanthine, respectively. Treatment with allopurinol or febuxostat alone resulted in 2-3 fold increase in hypoxanthine exposure. Relative changes of hypoxanthine were not significantly different in the presence versus absence of AR882. Increased excretion of xanthine and hypoxanthine was also observed in urine. AR882 was well tolerated in gout patients, showing a similar safety profile to that observed in healthy volunteer studies.Conclusion:AR882 dose alone had no effect on plasma or urine hypoxanthine and xanthine levels. AR882 contributed to a greater portion of the serum urate lowering effects when used in combination with XO inhibitors, and with 100% of patients achieving levels below 4 mg/dL when combined with allopurinol. The use of AR882 in combination with XO inhibitors may provide an option for preventing flares as well as tophi reduction in advanced patients.Disclosure of Interests:Zancong Shen Employee of: arthrosi therapeutics, Chris Colton Employee of: Arthrosi therapeutics Inc, Rongzi Yan Employee of: Arthrosi therapeutics Inc, Elizabeth Polvent Employee of: Arthrosi therapeutics Inc, Vijay Hingorani Consultant of: Arthrosi therapeutics Inc, Shunqi Yan Employee of: Arthrosi therapeutics Inc, Li-Tain Yeh Employee of: Arthrosi therapeutics Inc.
Urate-lowering drugs in the treatment of gout: The unknown about the known
