替沃扎尼滴眼液在健康志愿者和新生血管性年龄相关性黄斑变性患者中的I期研究。
Phase I Study of Tivozanib Eye Drops in Healthy Volunteers and Patients with Neovascular Age-Related Macular Degeneration.
作者信息
Gomi Fumi, Iida Tomohiro, Mori Ryusaburo, Horita Shinya, Nakamura Hiroaki, Nakajima Yu, Shiokawa Ayako, Takahashi Kanji
机构信息
Department of Ophthalmology, Hyogo Medical University, Nishinomiya, Hyogo, Japan.
Department of Ophthalmology, Tokyo Women's Medical University, Tokyo, Japan.
出版信息
Ophthalmol Sci. 2024 May 22;4(6):100553. doi: 10.1016/j.xops.2024.100553. eCollection 2024 Nov-Dec.
PURPOSE
To evaluate the safety, pharmacokinetics, and exploratory efficacy of tivozanib eye drops in healthy volunteers and patients with neovascular age-related macular degeneration (nAMD).
DESIGN
This multicenter group-sequential dose escalation phase I study consisted of a placebo-controlled double-masked study of healthy volunteers (cohorts 1 and 2) and an open-label study of patients with nAMD (cohort 3).
PARTICIPANTS
Healthy volunteers: Japanese or White men aged 20 to <50 years. Patients with nAMD with central subfield thickness (CST) ≥300 μm and best-corrected visual acuity score ≥23 letters in the study eye.
METHODS
In the single-dose cohort of healthy men (cohort 1: steps 1-5), 1 or 2 tivozanib eye drops (30 μL/drop, 5-minute interval; 0.5, 1.0, and 2.0 w/v%) or placebo were administered in 1 eye once. In the multiple-dose cohort of healthy men (cohort 2: steps 1-6), 1 or 2 tivozanib eye drops (0.5, 1.0, and 2.0 w/v%) or placebo were administered 3 times daily in 1 eye for 21 days. In the multiple-dose cohort of patients with nAMD (cohort 3, steps 1-3), 1 or 2 tivozanib eye drops (0.5 and 1.0 w/v%) were administered 3 times daily in 1 affected eye for 21 days.
MAIN OUTCOME MEASURES
The safety outcome measures included adverse events (AEs). The pharmacokinetic outcome was serum tivozanib concentration. Among the exploratory efficacy outcomes, CST was evaluated.
RESULTS
In total, 40, 48, and 28 participants were enrolled in cohorts 1, 2, and 3, respectively. Serious AEs did not occur in cohorts 1 to 3. The most frequent AE in multiple-dose cohorts was reversible punctate keratitis: placebo arm, 8.3% (healthy men, 1/12); tivozanib arm, 47.2% (healthy men, 17/36) and 14.3% (nAMD, 4/28). Serum tivozanib exposure increased dose-dependently and was similar in healthy men and patients with nAMD. In patients with nAMD, mean CST changes from baseline to day 22 were -27.6 ± 54.88 (0.5 w/v%; 1 drop, 3 times daily), -35.6 ± 49.64 (1.0 w/v%; 1 drop, 3 times daily), and -43.7 ± 55.19 μm (1.0 w/v%; 2 drops, 3 times daily).
CONCLUSIONS
Tivozanib eye drops showed a favorable safety profile in healthy Japanese and White men and Japanese patients with nAMD.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
目的
评估替沃扎尼滴眼液在健康志愿者和新生血管性年龄相关性黄斑变性（nAMD）患者中的安全性、药代动力学及探索性疗效。
设计
这项多中心组序贯剂量递增的I期研究包括对健康志愿者（队列1和2）进行的安慰剂对照双盲研究以及对nAMD患者（队列3）进行的开放标签研究。
参与者
健康志愿者：年龄在20至<50岁之间的日本或白人男性。研究眼中中心子场厚度（CST）≥300μm且最佳矫正视力得分≥23个字母的nAMD患者。
方法
在健康男性单剂量队列（队列1：步骤1 - 5）中，1或2滴替沃扎尼滴眼液（30μL/滴，间隔5分钟；0.5、1.0和2.0 w/v%）或安慰剂一次性滴入1只眼。在健康男性多剂量队列（队列2：步骤1 - 6）中，1或2滴替沃扎尼滴眼液（0.5、1.0和2.0 w/v%）或安慰剂每天3次滴入1只眼，持续21天。在nAMD患者多剂量队列（队列3，步骤1 - 3）中，1或2滴替沃扎尼滴眼液（0.5和1.0 w/v%）每天3次滴入1只患眼，持续21天。
主要观察指标
安全性观察指标包括不良事件（AE）。药代动力学指标是血清替沃扎尼浓度。在探索性疗效指标中，评估了CST。
结果
队列1、2和3分别共有40、48和28名参与者。队列1至3中未发生严重AE。多剂量队列中最常见的AE是可逆性点状角膜炎：安慰剂组，8.3%（健康男性，1/12）；替沃扎尼组，47.2%（健康男性，17/36）和14.3%（nAMD，4/28）。血清替沃扎尼暴露量呈剂量依赖性增加，在健康男性和nAMD患者中相似。在nAMD患者中，从基线到第22天的平均CST变化为-27.6±54.88（0.5 w/v%；1滴，每日3次）、-35.6±49.64（1.0 w/v%；1滴，每日3次）和-43.7±55.19μm（1.0 w/v%；2滴，每日3次）。
结论
替沃扎尼滴眼液在健康的日本和白人男性以及日本nAMD患者中显示出良好的安全性。
财务披露
专有或商业披露信息可在本文末尾的脚注和披露部分中找到。
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