Abstract
Purpose: Lifitegrast is approved in the United States for the treatment of dry eye disease (DED). We assessed lifitegrast's ocular distribution/pharmacokinetic profile in rabbits, and 14C-lifitegrast mass balance/excretion in dogs.Methods: Female pigmented rabbits received a single topical ocular dose of lifitegrast (Formulation No. 1, n = 25; No. 2, n = 25) per eye twice daily (target, 1.75 mg/eye/dose). Blood/ocular tissues were collected on day 5. Beagle dogs received single intravenous (n = 10; target, 3 mg, 262 μCi/animal) and ocular (n = 8, target, 3 mg, 30 μCi/eye) doses of 14C-lifitegrast (∼8 weeks between doses). Blood, excreta, and cage rinse/wipes were collected. Concentrations were measured by mass spectrometry/liquid scintillation counting. Pharmacokinetic analyses (noncompartmental) included maximum concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve from 0 to 8 h (AUC0–8).Results: In rabbits, lifitegrast Cmax and AUC0–8 were similar between formulations. Cmax was highest in ocular anterior segment tissues: 5,190–14,200 ng/g [conjunctiva (palpebral/bulbar), cornea, anterior sclera]. Posterior segment tissues had lower concentrations (0–826 ng/g). AUC0–8 followed a similar trend. Plasma concentrations were low (Cmax <18 ng/mL). Tissue/plasma tmax was ∼0.25–1 h. In dogs, after intravenous/ocular doses, 14C-lifitegrast was eliminated primarily through feces. Excreted radioactivity was mainly unchanged lifitegrast.Conclusions: High exposure of lifitegrast in rabbit ocular anterior segment tissues and low exposure in posterior segment tissues/plasma suggests that lifitegrast reaches target tissues for DED treatment, with low potential for off-target systemic/ocular effects. Excretion of unchanged 14C-lifitegrast suggests minimal drug metabolism in vivo. This is consistent with lifitegrast clinical trial efficacy/safety data.
Highlights
Dry eye disease (DED) is an ocular disorder associated with surface tissue damage and impaired tear production and is commonly encountered in clinical practice.[1]
Following repeated topical ocular BID dose administration of lifitegrast for 5 days in pigmented rabbits, distribution and exposure of lifitegrast was generally highest in the anterior ocular segment tissues, in particular the conjunctiva and cornea, while low concentrations of lifitegrast were observed in the posterior segment tissues (Fig. 3)
Following ocular administration in rabbits, the highest concentrations of lifitegrast are localized in anterior ocular segment tissues, in particular the conjunctiva and cornea, with low concentrations in the posterior segment tissues and plasma
Summary
Dry eye disease (DED) is an ocular disorder associated with surface tissue damage and impaired tear production and is commonly encountered in clinical practice.[1]. Current understanding of the mechanism of action of lifitegrast is that it decreases T cell-mediated inflammation associated with DED by blocking the interaction between the integrin LFA-1 and intercellular adhesion molecule 1 (ICAM-1), thereby preventing T cell activation and recruitment.[8,9] Lifitegrast is administered as a 5.0% ophthalmic solution (preservative free) applied to each eye twice daily (BID; *12 h apart)
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