| Summary: | 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
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