A randomized phase I clinical study of cis-urocanic acid eye drops in healthy adult subjects

Purpose: To evaluate safety, ocular tolerability and pharmacokinetics of 0.5% and 2.5% cis-urocanic acid (cis-UCA) eye drops. Methods: In this phase I, double-blinded, placebo-controlled trial, 37 healthy volunteers were randomized to three treatment arms: 0.5% cis-UCA (12 subjects), 2.5% cis-UCA (12 subjects) and placebo eye drops (13 subjects). In the first part, the subjects were dosed topically on a randomized eye with one drop three times at 7 +/- 1 hr intervals during 1 day. In the second part, the subjects self-administered three daily drops at 7 +/- 1 hr intervals on both eyes for 14 days. Physical examination of the eyes was performed seven times during the study. Tolerability of cis-UCA was assessed by ocular comfort rating questionnaire. Pharmacokinetic blood and urine samples were analysed under good laboratory practice (GLP). Results: All subjects completed both parts of the study. There were no significant adverse events (AEs). The most common treatment-related ocular AE was eye irritation (62.2% of subjects). Cis-UCA concentrations in plasma remained below the limit of quantification (0.195 mu g/ml) in all but two subjects. The fraction of the administered drug excreted into urine over the total collection period ranged from 3.2% to 61.6% of the last dose and from 1.1% to 20.5% of the daily dose. Conclusions: Topical ocular administration of cis-UCA solution is safe and apart from mild-and short-lasting eye irritation after administration well tolerated in healthy adult subjects. Topical ocular dosing leads to transient systemic exposure to cis-UCA that does not cause systemic AEs.