■为了评估安全性,药代动力学,对健康志愿者和新生血管性年龄相关性黄斑变性(nAMD)患者的观察和观察。
■这项多中心组顺序剂量递增I期研究包括健康志愿者的安慰剂对照双掩蔽研究(队列1和2)和nAMD患者的开放标签研究(队列3)。
■健康志愿者:20至50岁的日本或白人男性。研究眼中中心亚区厚度(CST)≥300μm且最佳矫正视力评分≥23个字母的nAMD患者。
■在健康男性的单剂量队列中(队列1:步骤1-5),1或2个tivozanib滴眼液(30μL/滴,5分钟间隔;0.5、1.0和2.0w/v%)或安慰剂在1只眼中给药一次。在健康男性的多剂量队列中(队列2:步骤1-6),每天在1只眼中给药1或2个tivozanib滴眼液(0.5、1.0和2.0w/v%)或安慰剂3次,共21天。在nAMD患者的多剂量队列中(队列3,步骤1-3),在1只受影响的眼睛中每天给药3次1或2只托伏扎尼滴眼剂(0.5和1.0w/v%),持续21天。
■安全性结果措施包括不良事件(AE)。药代动力学结果为血清托沃扎尼浓度。在探索性疗效结果中,对CST进行了评估。
■总共,40、48和28名参与者分别被纳入队列1、2和3。在队列1至3中未发生严重的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);tivozanib手臂,47.2%(健康男性,17/36)和14.3%(nAMD,4/28).在健康男性和nAMD患者中,血清替沃扎尼暴露呈剂量依赖性增加,并且相似。在nAMD患者中,从基线到第22天的平均CST变化为-27.6±54.88(0.5w/v%;1下降,每天3次),-35.6±49.64(1.0w/v%;1下降,每天3次),和-43.7±55.19μm(1.0w/v%;2滴,每天3次)。
Tivozanib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。
■专有或商业披露可在本文末尾的脚注和披露中找到。
UNASSIGNED: To evaluate the safety, pharmacokinetics, and exploratory efficacy of tivozanib eye drops in healthy volunteers and patients with neovascular age-related macular degeneration (nAMD).
UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: The safety outcome measures included adverse events (AEs). The pharmacokinetic outcome was serum tivozanib concentration. Among the exploratory efficacy outcomes, CST was evaluated.
UNASSIGNED: 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).
UNASSIGNED: Tivozanib eye drops showed a favorable safety profile in healthy Japanese and White men and Japanese patients with nAMD.
UNASSIGNED: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.