Hosoya T, Sasaki T, Hashimoto H, Sakamoto R, Ohashi T
Department of Pathophysiology and Therapy in Chronic Kidney Disease, Jikei University School of Medicine, Tokyo, Japan.
Medical R&D Division, Fuji Yakuhin Co., Ltd., Saitama, Japan.
J Clin Pharm Ther. 2016 Jun;41(3):298-305. doi: 10.1111/jcpt.12392. Epub 2016 Apr 15.
In Japan, although topiroxostat, a selective xanthine oxidoreductase inhibitor, has been used for the treatment of patients with hyperuricemia including gout, no published randomized controlled studies evaluating the dose-dependent relationship with respect to the serum urate-lowering efficacy have been reported. The aim of this study was to evaluate the dose-dependent relationship with serum urate-lowering efficacy and safety of topiroxostat in Japanese hyperuricemic patients including gout.
We conducted an exploratory, phase 2a, multicentre, randomized, double-blind, 8-week, placebo-controlled study in Japanese hyperuricemic patients with or without gout. The study arms were placebo and topiroxostat 40, 60, 80 or 120 mg/day. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit.
One hundred and eighty-seven eligible patients were randomized and 186 received at least one dose of the study drug. The study results demonstrated a dose-dependent serum urate reduction effect ranging from 40 to 120 mg/day (P < 0·001, Jonckheere-Terpstra test). The mean per cent change in serum urate level from baseline at the final visit was -30·8% in the 120-mg group and 1·6% with placebo, with a between-group difference of -32·4% ([95% confidence interval, -38·9% to -25·9%]; P < 0·001). Incidences of overall adverse events (AEs) in the topiroxostat groups were comparable to those in the placebo group; however, the incidence of AEs in the 120-mg group was statistically lower than that in the placebo group. The incidences of gouty arthritis were not statistically but numerically higher in the topiroxostat 80- and 120-mg groups.
A dose-dependent serum urate-lowering efficacy of topiroxostat was observed in Japanese hyperuricemic male patients with or without gout. Further clinical studies aimed at evaluating the long-term safety and clinical efficacy are warranted.
在日本，虽然选择性黄嘌呤氧化还原酶抑制剂托匹司他已用于治疗包括痛风在内的高尿酸血症患者，但尚未有已发表的随机对照研究评估其降尿酸疗效的剂量依赖性关系。本研究的目的是评估托匹司他在包括痛风患者在内的日本高尿酸血症患者中降尿酸疗效及安全性的剂量依赖性关系。
我们对有或无痛风的日本高尿酸血症患者开展了一项探索性2a期多中心随机双盲8周安慰剂对照研究。研究分组为安慰剂组以及托匹司他40、60、80或120mg/天组。主要疗效终点是血清尿酸水平从基线至末次访视的变化百分比。
187例符合条件的患者被随机分组，186例接受了至少一剂研究药物。研究结果显示，托匹司他40至120mg/天具有剂量依赖性降尿酸效果（Jonckheere-Terpstra检验，P<0.001）。末次访视时血清尿酸水平较基线的平均变化百分比在120mg组为-30.8%，安慰剂组为1.6%，组间差异为-32.4%（[95%置信区间，-38.9%至-25.9%]；P<0.001）。托匹司他各治疗组的总体不良事件（AE）发生率与安慰剂组相当；然而，120mg组的AE发生率在统计学上低于安慰剂组。痛风性关节炎的发生率在托匹司他80mg和120mg组虽无统计学差异，但数值上更高。
在有或无痛风的日本高尿酸血症男性患者中观察到托匹司他具有剂量依赖性降尿酸疗效。有必要开展进一步的临床研究以评估其长期安全性和临床疗效。
