A phase 1, open-label, single-arm study evaluating the ocular safety of OTX-101 and systemic absorption of cyclosporine in healthy human volunteers
Received 18 September 2018
Accepted for publication 29 January 2019
Published 5 April 2019 Volume 2019:13 Pages 591—596
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Scott Fraser
Paul M Karpecki,1,2 Sidney L Weiss,3 William G Kramer,4 Patrick O’Connor,5 David Evans,6 Josh Johnston,7 April L Jasper,8 Angela Justice,9 Abayomi B Ogundele,9 Doug Devries10
1Kentucky Eye Institute, Lexington, KY, USA; 2Gaddie Eye Centers, Louisville, KY, USA; 3i-novion, Inc., Randolph, NJ, USA; 4Kramer Consulting, LLC, North Potomac, MD, USA; 5Auven Therapeutics, Delray Beach, FL, USA; 6Total Eye Care, Memphis, TN, USA; 7Georgia Eye Partners, Atlanta, GA, USA; 8Advanced Eyecare Specialists, West Palm Beach, FL, USA; 9Sun Ophthalmics, Sun Pharmaceutical Industries, Ltd., Princeton, NJ, USA; 10Eye Care Associates of Nevada, Sparks, NV, USA
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 [Cmax, ng/mL], time to Cmax [Tmax, hours]), and area under the concentration-time curve from 0 to the last measurement [AUC(0–t), 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 Cmax was 0.17±0.02 ng/mL, Tmax was 1.5±0.58 hours, and AUC(0–t) 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.
Keywords: dry eye disease, cyclosporine, pharmacokinetic, systemic exposure
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]