Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects.
Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects.
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DOI：
10.2147/dddt.s140658
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Hall JW
中科院分区：
文献类型：
--
作者：
Shen Z;Gillen M;Miner JN;Bucci G;Wilson DM;Hall JW
Verinurad(RDEA3170)是一种临床开发中的选择性尿酸重吸收抑制剂，用于治疗痛风和无症状的高尿酸血症。本研究的目的是评估马鞭草在健康成年男性体内的药代动力学、药效学和耐受性。这是一项I期随机、双盲、安慰剂对照、单次和多次递增剂量研究。8名男性受试者在禁食或进食状态下接受单剂量的马鞭草或安慰剂的口服；10-12名男性受试者的小组在禁食状态下接受每日一次的马鞭草或安慰剂的递增剂量，为期10天。对连续的血样和尿样进行马鞭草酸和尿酸检测。安全性通过不良事件(AE)报告、实验室测试、生命体征和心电图(ECG)进行评估。共有81名成年男性完成了这项研究。单次给药后，最大观察血药浓度(Cmax)和血药浓度-时间曲线下面积(AUC)均呈剂量比例增加，禁食和服药后Cmax分别出现在0.5~0.75小时和1.25小时。食物使AUC值下降了23%，Cmax下降了37%，−下降了53%。在每日多次给药后，有少量的马鞭草积累。Verinurad使血清尿酸水平降低了高达62%(单剂40毫克)和61%(10毫克，多次剂量)。尿酸排泄量的增加在给药后前6小时最大，24小时仍明显，≥剂量为≥2 mg。威力诺在所有剂量下耐受性都很好。没有严重的脑血栓栓塞症、严重的脑血栓栓塞症、因脑血栓栓塞症引起的中断、临床显著的实验室或心电图异常的报道。单剂和多剂马鞭草耐受性好，吸收快，暴露剂量成比例。Verinurad增加了尿尿酸排泄，并导致血清尿酸持续下降。这些数据支持将每日一次的马鞭草作为痛风治疗的进一步临床评估。
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 (Cmax) and area under the plasma concentration–time curve (AUC) increased in a dose-proportional manner; Cmax occurred at 0.5–0.75 hours and 1.25 hours in the fasted and fed states, respectively. Food decreased AUC by 23% and Cmax 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.