Shen Zancong, Gillen Michael, Miner Jeffrey N, Bucci Gail, Wilson David M, Hall Jesse W
Ardea Biosciences, Inc., San Diego, CA.
AstraZeneca, Gaithersburg, MD, USA.
Drug Des Devel Ther. 2017 Jul 7;11:2077-2086. doi: 10.2147/DDDT.S140658. eCollection 2017.
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.
维立尿酸（RDEA3170）是一种选择性尿酸重吸收抑制剂，正处于治疗痛风和无症状高尿酸血症的临床开发阶段。本研究的目的是评估维立尿酸在健康成年男性中的药代动力学、药效学和耐受性。
这是一项I期随机双盲安慰剂对照单剂量和多剂量递增研究。八名男性受试者组成的小组在禁食或进食状态下接受单次口服维立尿酸或安慰剂；10 - 12名男性受试者组成的小组在禁食状态下接受递增剂量的维立尿酸或安慰剂，每日一次，持续10天。对系列血液和尿液样本进行维立尿酸和尿酸检测。通过不良事件（AE）报告、实验室检查、生命体征和心电图（ECG）评估安全性。
共有81名成年男性完成了该研究。单次服用维立尿酸后，观察到的最大血浆浓度（Cmax）和血浆浓度 - 时间曲线下面积（AUC）呈剂量比例增加；禁食和进食状态下Cmax分别在0.5 - 0.75小时和1.25小时出现。食物使AUC降低23%，Cmax降低37% - 53%。每日多次给药后维立尿酸有适度蓄积。维立尿酸使血清尿酸水平降低高达62%（单剂量40 mg）和61%（多剂量10 mg）。给药后最初6小时内尿酸尿排泄增加最为显著，对于维立尿酸剂量≥2 mg，≥24小时仍很明显。所有剂量的维立尿酸耐受性良好。未报告严重AE、重度AE、因AE停药或具有临床意义的实验室或ECG异常。
单次和多次服用维立尿酸耐受性良好，吸收迅速，暴露量充足。维立尿酸增加了尿尿酸排泄，并导致血清尿酸持续降低。这些数据支持将每日一次的维立尿酸作为痛风治疗药物进行进一步临床评估。
