一项1期、开放标签、单臂研究，评估OTX-101在健康人类志愿者中的眼部安全性以及环孢素的全身吸收情况。

A phase 1, open-label, single-arm study evaluating the ocular safety of OTX-101 and systemic absorption of cyclosporine in healthy human volunteers.

作者信息

Karpecki Paul M, Weiss Sidney L, Kramer William G, O'Connor Patrick, Evans David, Johnston Josh, Jasper April L, Justice Angela, Ogundele Abayomi B, Devries Doug

机构信息

Kentucky Eye Institute, Lexington, KY, USA,

Gaddie Eye Centers, Louisville, KY, USA,

出版信息

Clin Ophthalmol. 2019 Apr 5;13:591-596. doi: 10.2147/OPTH.S187945. eCollection 2019.

DOI:10.2147/OPTH.S187945

PMID:31040639

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6454998/

Abstract

PURPOSE

To evaluate the ocular safety of OTX-101 0.09% - a novel, nanomicellar, clear, aqueous solution of cyclosporine (CsA) - and to determine the systemic exposure to CsA following ophthalmic administration.

PATIENTS AND METHODS

Healthy volunteers ≥18 years of age were recruited for participation in this phase 1, open-label, single-center, single-arm, study. Subjects received one drop of OTX-101 0.09% in each eye every 12 hours for 7 days, and once on day 8. Blood samples were collected predose, and 0.25, 0.5, 1, 2, 4, 8, and 12 hours post-first dose on day 1 and day 8. CsA levels in whole blood samples were analyzed using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters (maximal whole blood concentration [C, ng/mL], time to C [T, hours]), and area under the concentration-time curve from 0 to the last measurement [AUC, h·ng/mL]) were calculated using noncompartmental analysis. Safety assessments included subject-reported adverse events (AEs), vital signs, visual acuity, intraocular pressure measurement, biomicroscopy, and direct ophthalmoscopy.

RESULTS

A total of 16 subjects were enrolled; 15 subjects completed the study. Blood sample analysis indicated limited systemic exposure to CsA; three subjects had a CsA concentration greater than or equal to the lower limit of quantitation (LLOQ) on day 1; only four subjects had three consecutive CsA concentration measurements ≥LLOQ on day 8; the mean±SD for C was 0.17±0.02 ng/mL, T was 1.5±0.58 hours, and AUC was 0.53±0.06 h·ng/mL. Three subjects reported three AEs (eye pain, eye pruritis, and eye irritation) during the study. No clinically significant changes in the safety assessments were noted.

CONCLUSION

The OTX-101 formulation was well tolerated. Systemic exposure to CsA was negligible in healthy volunteers after twice-daily ocular administration. No evidence for systemic accumulation of CsA was observed.

摘要

目的

评估新型纳米胶束、澄清的环孢素（CsA）滴眼液OTX-101 0.09%的眼部安全性，并确定眼部给药后CsA的全身暴露情况。

患者与方法

招募年龄≥18岁的健康志愿者参与这项1期、开放标签、单中心、单臂研究。受试者每12小时每只眼滴入一滴OTX-101 0.09%，共7天，并在第8天给药一次。在给药前以及第1天和第8天首次给药后的0.25、0.5、1、2、4、8和12小时采集血样。使用液相色谱-串联质谱法分析全血样本中的CsA水平。采用非房室分析计算药代动力学参数（最大全血浓度[C，ng/mL]、达到C的时间[T，小时]）以及从0至最后一次测量的浓度-时间曲线下面积[AUC，h·ng/mL]）。安全性评估包括受试者报告的不良事件（AE）、生命体征、视力、眼压测量、生物显微镜检查和直接检眼镜检查。

结果

共纳入16名受试者；15名受试者完成了研究。血样分析表明CsA的全身暴露有限；3名受试者在第1天的CsA浓度大于或等于定量下限（LLOQ）；仅4名受试者在第8天有3次连续的CsA浓度测量值≥LLOQ；C的平均值±标准差为0.17±0.02 ng/mL，T为1.5±0.58小时，AUC为0.53±0.06 h·ng/mL。3名受试者在研究期间报告了3起AE（眼痛、眼瘙痒和眼刺激）。安全性评估未发现临床显著变化。