Pharmacokinetics, Pharmacodynamics, and Tolerability of Concomitant Multiple Dose Administration of Verinurad (RDEA3170) and Allopurinol in Adult Male Subjects With Gout

Abstract

Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for treatment of hyperuricemia and gout. This phase 1b, multiple‐dose, drug‐drug interaction study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in combination with allopurinol. Adult males with gout were randomized to receive once‐daily oral doses of allopurinol 300 mg or verinurad 10 mg alone for 7 days, allopurinol 300 mg + verinurad 10 mg on days 8 to 14, and the alternative single agent on days 15 to 21. Colchicine 0.6 mg was taken prophylactically for gout flares. Plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol (allopurinol active metabolite), colchicine (plasma only), and uric acid. Safety was assessed by adverse events (AEs) and laboratory tests. Verinurad plasma exposure was unaffected by allopurinol. Verinurad increased the maximum observed plasma concentration (Cmax) for allopurinol by 33%; the area under the plasma concentration‐time curve (AUC) was unaffected. Oxypurinol Cmax and AUC were reduced 32% and 38%, respectively, by verinurad. Colchicine plasma exposure was unaltered by verinurad. The maximum decrease in serum urate was greater with verinurad + allopurinol (65%) than with verinurad (51%) or allopurinol (43%) alone. Compared with the baseline rate, the maximum rate of uric acid excreted in urine was +56% with verinurad, −46% with allopurinol, and unchanged with verinurad + allopurinol. No serious AEs, discontinuations due to AEs, or clinically significant laboratory abnormalities were noted. Despite decreased systemic exposure of allopurinol and oxypurinol in the presence of verinurad, the combination resulted in greater serum urate reduction compared with either drug alone and was well tolerated at the studied doses.

Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy Japanese and non-Asian male subjects

“…The increased urinary excretion of uric acid by verinurad may have the potential to induce uric acid microcrystallization in the renal tubules, which could increase the risk for renal-related AEs. In Phase 1 clinical trials with verinurad combined with an XOI (which reduces uric acid production), urinary excretion of uric acid was reduced, 19 , 20 which may reduce risk of microcrystallization. Reduced urinary uric acid excretion with the addition of an XOI to a URAT1 inhibitor was also seen with lesinurad, where low rates of kidney stones were observed with lesinurad + XOI treatment in Phase 3 clinical trials.…”

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

“…Verinurad concentrations in plasma and urine and febuxostat concentrations in plasma were measured by Ardea Biosciences, Inc. (San Diego, CA, USA). Plasma samples were extracted by protein precipitation and analytes quantified by high-performance liquid chromatography– tandem mass spectrometry [ 31 , 32 ]. Urine samples were prepared by dilution with water and quantified by high-performance liquid chromatography–tandem mass spectrometry.…”

Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Verinurad, a Selective Uric Acid Reabsorption Inhibitor

“…All analytical methods were validated following US Food and Drug Administration bioanalytical method validation guidance [ 31 ]. The analytical methodology for the quantitation of verinurad and metabolite M1 in plasma samples was a combination method similar to the methodology described by Kankam et al [ 22 ], although that methodology did not include M1. When M1 was included in the methodology, it (and its internal standard, IS) chromatographed as diastereomers and each peak was integrated and the resulting areas summed for concentration determination.…”

“…The potency of verinurad together with its pharmacokinetic properties may enable it to be used as a low-dose drug, with potentially less drug interaction issues in gout patients receiving concurrent treatments for comorbidities such as hypertension, cardiovascular disease, diabetes, and obesity. The combination of verinurad with an XOI results in a urinary uric acid profile that may offer a low potential for renal adverse effects [ 22 ] while also lowering sUA to a greater extent than either agent alone at the same or even higher monotherapy doses [ 23 – 25 ].…”