which is soluble in water.
Xiidra (lifitegrast ophthalmic solution) 5% is a lymphocyte function-associated antigen-1 ( LFA-1) antagonist supplied as a sterile, clear, colorless to slightly brownish-yellow colored, isotonic solution of lifitegrast with a pH of 7.0–8.0 and an osmolality range of 200–330 mOsmol/kg.
Xiidra contains Active: lifitegrast 50 mg/mL; Inactives: sodium chloride, sodium phosphate dibasic anhydrous, sodium thiosulfate pentahydrate, sodium hydroxide and/or hydrochloric acid (to adjust pH) and water for injection.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of ActionLifitegrast binds to the integrin lymphocyte function-associated antigen-1 (LFA-1), a cell surface protein found on leukocytes and blocks the interaction of LFA-1 with its cognate ligand intercellular adhesion molecule-1 (ICAM-1). ICAM-1 may be overexpressed in corneal and conjunctival tissues in dry eye disease. LFA-1/ICAM-1 interaction can contribute to the formation of an immunological synapse resulting in T-cell activation and migration to target tissues. In vitro studies demonstrated that lifitegrast may inhibit T-cell adhesion to ICAM-1 in a human T-cell line and may inhibit secretion of inflammatory cytokines in human peripheral blood mononuclear cells. The exact mechanism of action of lifitegrast in dry eye disease is not known.
12.3 PharmacokineticsIn a subset of dry eye disease patients (n=47) enrolled in a Phase 3 trial, the pre-dose (trough) plasma concentrations of lifitegrast were measured after 180 and 360 days of topical ocular dosing (1 drop twice daily) with Xiidra (lifitegrast ophthalmic solution) 5%. A total of nine (9) of the 47 patients (19%) had plasma lifitegrast trough concentrations above 0.5 ng/mL (the lower limit of assay quantitation). Trough plasma concentrations that could be quantitated ranged from 0.55 ng/mL to 3.74 ng/mL.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Animal studies have not been conducted to determine the carcinogenic potential of lifitegrast.
Mutagenesis
Lifitegrast was not mutagenic in the in vitro Ames assay. Lifitegrast was not clastogenic in the in vivo mouse micronucleus assay. In an in vitro chromosomal aberration assay using mammalian cells (Chinese hamster ovary cells), lifitegrast was positive at the highest concentration tested, without metabolic activation.
Impairment of fertility
Lifitegrast administered at intravenous (IV) doses of up to 30 mg/kg/day (5400-fold the human plasma exposure at the recommended human ophthalmic dose (RHOD) of lifitegrast ophthalmic solution, 5%) had no effect on fertility and reproductive performance in male and female treated rats.
14 CLINICAL STUDIES
The safety and efficacy of lifitegrast for the treatment of dry eye disease were assessed in a total of 1181 patients (1067 of which received lifitegrast 5%) in four 12-week, randomized, multi-center, double-masked, vehicle-controlled studies. Patients were randomized to Xiidra or vehicle (placebo) in a 1:1 ratio and dosed twice a day. Use of artificial tears was not allowed during the studies. The mean age was 59 years (range, 19–97 years). The majority of patients were female (76%). Enrollment criteria included, minimal signs (i.e., Corneal Fluorescein Staining (CFS) and non-anesthetized Schirmer Tear Test (STT)) and symptoms (i.e., Eye Dryness Score (EDS) and Ocular Discomfort Score (ODS)) severity scores at base |
