Bayer AG, Pharmaceuticals, Berlin and Wuppertal, Germany.
SocraTec R&D GmbH, Erfurt, Germany.
Br J Clin Pharmacol. 2018 May;84(5):865-875. doi: 10.1111/bcp.13502. Epub 2018 Mar 1.
Regorafenib is a multikinase inhibitor under investigation for use in neovascular age-related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy volunteers to provide information on safety, tolerability and systemic exposure.
This was a single-centre, randomized, double-masked, parallel-group, dose-escalation, placebo-controlled study. Subjects received regorafenib eye drops (30 mg ml , 25 μl) as a 0.75 mg single dose (Cohort 1), 0.75 mg twice daily (bid) or thrice daily (tid) over 14 days (Cohorts 2 and 3, respectively), 1.5 mg tid unilaterally for 3 days, then bilaterally for up to 14 days (Cohort 4), or placebo. Plasma samples were taken to estimate systemic exposure. Safety and functional assessments were performed throughout the study.
Thirty-six subjects received regorafenib and 12 received placebo. Regorafenib was safe and well tolerated over the dose range. No pathological changes occurred in the anterior, vitreous or posterior eye compartments. Mild eyelid redness, oedema and conjunctival hyperaemia were observed across all regorafenib cohorts; these were comparable with the effects seen with placebo. Predominant symptoms were blurred vision in the active and placebo groups. Systemic safety evaluations showed no clinically relevant findings. Absolute systemic exposure after multiple administrations of regorafenib eye drops at a dose of 0.75 mg was 600-700-fold lower than after multiple oral administration of 160 mg day , the dose approved in cancer indications.
These results indicate a favourable safety and tolerability profile of regorafenib eye drops up to 30 mg ml tid for use in clinical studies.
regorafenib 是一种正在研究用于新生血管性年龄相关性黄斑变性的多激酶抑制剂。在这项 I 期研究中，向健康志愿者给予regorafenib 滴眼液，以提供安全性、耐受性和全身暴露方面的信息。
这是一项单中心、随机、双盲、平行组、剂量递增、安慰剂对照研究。受试者接受 regorafenib 滴眼液（30mg/ml，25μl），单次剂量 0.75mg（第 1 队列）、每日 2 次（bid）或每日 3 次（tid）共 14 天（第 2 和第 3 队列）、单侧每日 3 次 1.5mg 共 3 天，然后双侧共 14 天（第 4 队列）或安慰剂。采集血浆样本以估计全身暴露量。在整个研究过程中进行安全性和功能评估。
36 名受试者接受了 regorafenib 治疗，12 名受试者接受了安慰剂治疗。在剂量范围内，regorafenib 安全且耐受性良好。前房、玻璃体或后房眼部均未发生病理性改变。所有 regorafenib 队列均观察到轻度眼睑发红、水肿和结膜充血；这些与安慰剂的效果相当。主要症状是活跃组和安慰剂组的视力模糊。全身安全性评估未发现有临床意义的发现。在剂量为 0.75mg 时多次给予 regorafenib 滴眼液后的全身暴露量绝对水平比批准用于癌症适应证的 160mg 日多次口服给药低 600-700 倍。
这些结果表明，在临床研究中，高达 30mg/ml tid 的 regorafenib 滴眼液具有良好的安全性和耐受性。
