Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects

• Published in: Drug design, development and therapy development and therapy, 2017-01, Vol.11, p.2077-2086
• Main Authors: Shen, Zancong, Gillen, Michael, Miner, Jeffrey N, Bucci, Gail, Wilson, David M, Hall, Jesse W
• Format: Article
• Language: English
• Subjects: Abnormalities; Adolescent; Adult; Arthritis; Clinical medicine; Clinical trials; Dosage; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Drug metabolism; EKG; Electrocardiography; Employees; Enzyme inhibitors; Excretion; Female; Food; Gout; Healthy Volunteers; Humans; Hyperuricemia; Inhibitors; Intestinal Absorption; Laboratories; Laboratory tests; Male; Males; Metabolic Clearance Rate; Middle Aged; Original Research; Panels; Pharmacodynamics; Pharmacokinetics; Pharmacological research; Pharmacology; Reabsorption; Rheumatism; selective uric acid reabsorption inhibitor; serum urate; Uric acid; Uric Acid - metabolism; Uric Acid - urine; Uricosuric Agents - adverse effects; Uricosuric Agents - pharmacokinetics; Uricosuric Agents - pharmacology; urinary uric acid; Urine; Young Adult
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/dddt.s140658

Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy adult males. This was a Phase I, randomized, double-blind, placebo-controlled, single and multiple ascending dose study. Panels of eight male subjects received a single oral dose of verinurad or placebo in either a fasted or fed state; panels of 10-12 male subjects received ascending doses of once-daily verinurad or placebo in a fasted state for 10 days. Serial blood and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs). A total of 81 adult males completed the study. Following single doses of verinurad, maximum observed plasma concentration (C ) and area under the plasma concentration-time curve (AUC) increased in a dose-proportional manner; C occurred at 0.5-0.75 hours and 1.25 hours in the fasted and fed states, respectively. Food decreased AUC by 23% and C by 37%-53%. There was a modest accumulation of verinurad following multiple daily doses. Verinurad reduced serum urate levels by up to 62% (40 mg, single dose) and 61% (10 mg, multiple dose). The increase in urinary excretion of uric acid was greatest in the first 6 hours after dosing and was still evident ≥24 hours for verinurad doses ≥2 mg. Verinurad was well tolerated at all doses. No serious AEs, severe AEs, discontinuations due to AEs, or clinically significant laboratory or ECG abnormalities were reported. Single and multiple doses of verinurad were well tolerated, absorption was rapid, and exposure was dose proportional. Verinurad increased urinary uric acid elimination and resulted in sustained reductions in serum urate. These data support further clinical evaluation of once-daily verinurad as a treatment for gout.