Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study

Abstract

ObjectivesVerinurad (RDEA3170) is a high affinity, selective uric acid transporter (URAT1) inhibitor indevelopment for treating gout and asymptomatic hyperuricaemia. This phase IIa study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad combined with allopurinol versus allopurinol alone in adults with gout.MethodsForty-one subjects were randomised into two cohorts of verinurad (2.5–20 mg) plus allopurinol (300 mg once daily) versus allopurinol 300 mg once daily, 600 mg once daily or 300 mg twice daily alone. Each treatment period was 7 days. Serial plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol and uric acid.ResultsSerum pharmacodynamic data pooled across cohorts demonstrated maximum per cent decreases in serum urate (sUA) from baseline (Emax) at 7–12 hours after verinurad plus allopurinol treatment. Combination treatment decreased sUA in dose-dependent manner: least-squares means Emax was 47%, 59%, 60%, 67%, 68% and 74% for verinurad doses 2.5, 5, 7.5, 10, 15 and 20 mg plus allopurinol 300 mg once daily, versus 40%, 54% and 54% for allopurinol 300 mg once daily, 600 mg once daily and 300 mg twice daily. Verinurad had no effect on allopurinol plasma pharmacokinetics, but decreased oxypurinol Cmax by 19.0%–32.4% and area under the plasma concentration–time curve from time zero to the last measurable time point by 20.8%–39.2%. Verinurad plus allopurinol was well tolerated with no serious adverse events (AEs), AE-related withdrawals or renal-related events. Laboratory values showed no clinically meaningful changes.ConclusionVerinurad coadministered with allopurinol produced dose-dependent decreases in sUA. All dose combinations of verinurad and allopurinol were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout.Trial registration numberNCT02498652.

Safety and efficacy of verinurad, a selective URAT1 inhibitor, for the treatment of patients with gout and/or asymptomatic hyperuricemia in the United States and Japan: Findings from two phase II trials

“…The results of this trial further the concept that potent URAT1 inhibitors without prolonged activities in humans, such as lesinurad and verinurad, must be given with an XOI that simultaneously reduces the production of uric acid. To this end, no subjects in the trials where verinurad was combined with an XOI have shown increases in sCr !1.5 Â baseline [24][25][26]. These results are consistent with those of lesinurad, which is associated with significant increases in renal AEs when given as monotherapy [10].…”

“…However, the possibility that excessive uric acid excretion is associated with nephropathy may mean that verinurad should be administered with an agent that reduces uric acid production and minimizes uric acid in the kidney. The combination of verinurad with an XOI has been successfully studied elsewhere [24][25][26].…”

Verinurad combined with febuxostat in Japanese adults with gout or asymptomatic hyperuricaemia: a phase 2a, open-label study

“…These observations suggest that combining two treatments with different mechanisms of action can reduce sUA levels more consistently and lead to higher target achievement rates than a single agent alone at higher doses. Two other phase 2a studies investigating verinurad in combination with febuxostat or allopurinol, which were performed in Caucasian subjects with gout, also reported superior sUA lowering for the combination versus XOI treatment alone [ 27 , 28 ].…”

Therapeutic Strategies for the Treatment of Chronic Hyperuricemia: An Evidence-Based Update

“…In vivo, a single dose of verinurad 40 mg has demonstrated to lower SUA by up to 62% whereas multiple doses of verinurad 10 mg have reached a reduction in SUA levels approximately of 61%, being well tolerated at all doses and with no serious adverse events nor significant laboratory or ECG abnormalities reported [ 94 ]. Moreover, in coadministration with allopurinol 300 mg, verinurad (2.5–20 mg) has been shown to produce a dose-dependent decrease in SUA, with no instances of serum creatinine elevation [ 95 ].…”