Metabolism and Disposition of Verinurad, a Uric Acid Reabsorption Inhibitor, in Humans

Abstract

Verinurad (RDEA3170) is a second generation selective uric acid reabsorption inhibitor for the treatment of gout and asymptomatic hyperuricemia. Following a single oral solution of 10-mg dose of [C]verinurad (500 Ci), verinurad was rapidly absorbed with a median time to occurrence of maximum observed concentration (T) of 0.5 hours and terminal half-life of 15 hours. In plasma, verinurad constituted 21% of total radioactivity. Recovery of radioactivity in urine and feces was 97.1%. Unchanged verinurad was the predominant component in the feces (29.9%), whereas levels were low in the urine (1.2% excreted). Acylglucuronide metabolites M1 (direct glucuronidation) and M8 (glucuronidation of N-oxide) were formed rapidly after absorption of verinurad with terminal half-life values of approximately 13 and 18 hours, respectively. M1 and M8 constituted 32% and 31% of total radioactivity in plasma and were equimolar to verinurad on the basis of AUC ratios. M1 and M8 formed in the liver were biliary cleared with complete hydrolysis in the GI tract, as metabolites were not detected in the feces and/or efflux across the sinusoidal membrane; M1 and M8 accounted for 29.2% and 32.5% of the radioactive dose in urine, respectively. In vitro studies demonstrated that CYP3A4 mediated the formation of the N-oxide metabolite (M4), which was further metabolized by glucuronyl transferases (UGTs) to form M8, as M4 was absent in plasma and only trace levels were present in the urine. Several UGTs mediated the formation of M1, which could also be further metabolized by CYP2C8. Overall, the major clearance route of verinurad is metabolism via UGTs and CYP3A4 and CYP2C8.

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

“…Verinurad studies in healthy volunteers show that ~64% of a single oral 10 mg dose is absorbed, with a median time to maximum observed plasma concentration (T max ) of 0.5 hours and a terminal half-life of 15 hours. 25 …”

Pharmacokinetics, Pharmacodynamics, and Tolerability of Concomitant Administration of Verinurad and Febuxostat in Healthy Male Volunteers

“…20 The drug-drug interaction (DDI) potential of verinurad is low, as it does not inhibit the major CYPs (Ardea Biosciences, Inc., data on file). Several UGTs (1A3, 2B4, 2B7, and 2B17) glucuronidate verinurad to form acyl glucuronide M1, while CYP3A4 is involved in the formation of an Noxide.…”

“…The formation of M8 occurs via sequential glucuronidation of M4 to M8 or by oxidation of M1 to M8 via CYP2C8. 20 The drug-drug interaction (DDI) potential of verinurad is low, as it does not inhibit the major CYPs (Ardea Biosciences, Inc., data on file). The DDI potential of verinurad as a victim is also low, as its disposition involves several metabolic enzymes.…”

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

“…Verinurad is predominantly eliminated by hepatic metabolism via glucuronyl transferase and CYP3A4 metabolism, with about 2% of the parent drug excreted unchanged in urine [ 26 ]. In this study, plasma exposure of verinurad and its acyl glucuronides increased with the extent of decreased renal function.…”

“…M8 formation can also occur via CYP2C8-mediated metabolism of M1. Metabolites M1 and M8 are the predominant circulating metabolites of verinurad and are devoid of URAT1 activity [ 26 ]. Verinurad is predominantly eliminated by hepatic metabolism, with about 2% of parent drug excreted unchanged in urine [ 21 ].…”