Abstract
Purpose :
To assess ocular distribution and pharmacokinetics (PK) after repeat topical ocular administration of two Phase 3 formulations of lifitegrast in pigmented rabbits. Lifitegrast is a lymphocyte function-associated antigen-1 (LFA-1) antagonist recently approved in the US for treatment of signs and symptoms of dry eye disease (DED).
Methods :
Female pigmented rabbits received a single topical ocular dose of lifitegrast (formulation #1, n=25; #2, n=25) in each eye, twice daily for 4 days and once on day 5, at a target dose level of 1.75 mg/eye/dose. Animals were euthanized on day 5; blood and ocular tissues were collected from 5 animals per formulation per time point at 0.25, 0.5, 1, 3, and 8 h after last dose. Liquid chromatography tandem mass spectrometry was used to measure lifitegrast concentrations. PK analyses (non-compartmental) included determination of maximum concentration (Cmax), time to maximum concentration (tmax), and area under concentration-time curve from 0 to 8 h (AUC0-8).
Results :
Cmax and AUC0-8 for ocular tissues and plasma were similar between the formulations. Lifitegrast concentrations were highest in the ocular anterior segment tissues, with Cmax for the conjunctiva (palpebral and bulbar), cornea, and sclera (anterior) in the range 5190–14200 ng/g. Concentrations were lower in other ocular tissues, with the next highest Cmax 826 ng/g for the sclera (posterior). Very low/non-detectable lifitegrast concentrations (0–36.0 ng/g) were observed in the lens, optic nerve, retina and vitreous humor. Across all tissues, tmax was ~0.25–1 h, indicating rapid absorption after administration. Overall exposure (AUC0-8) for both formulations was highest in the conjunctiva (palpebral), followed by the cornea, sclera (anterior), conjunctiva (bulbar), sclera (posterior), iris-ciliary body, aqueous humor, and choroid-retinal pigmented epithelium. The plasma had low lifitegrast concentrations (Cmax: formulation #1, 17.4 ng/mL; #2, 9.52 ng/mL), and tmax (#1 and #2, 0.25 h).
Conclusions :
The high exposure of lifitegrast in rabbit ocular anterior segment tissues, and low exposure in posterior segment tissues and plasma, suggests that lifitegrast is likely to reach the target tissues for DED treatment while having low potential for off-target systemic or ocular effects. The PK profile of lifitegrast was similar between formulations.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.