By preventing the interaction of two crucial cell surface proteins—lymphocyte function-associated antigen 1 and intercellular adhesion molecule 1—ligifestegrast (SAR 1118) reduces T cell-mediated inflammation and lowers the total inflammatory response [1]. Lifitegrast has an IC50 of 2.98 nM, which results in a substantial inhibition of Jurkat T cell adhesion to ICAM-1[1].

Lifitegrast (SAR 1118) is best used with 1% solution applied two or three times prior to use. It has strong anti-inflammatory activity against corneal inflammation caused by antibiotic-killed Pseudomonas aeruginosa and Staphylococcus aureus in the presence of silicone hydrogel lenses [2]. Three times a day administration of Lifitegrast (SAR 1118) eye drops results in therapeutic levels of the substance in the retina and may lessen diabetic-related retinal complications [3].

Absorption, Distribution and Excretion
The mean peak plasma concentration (Cmax) of 1.70 ng/mL is reached within 15 minutes after administration. Quantifiable trough plasma concentrations range from 0.55 ng/mL to 3.74 ng/mL. Observations indicate limited systemic exposure, but significant clinical efficacy. Mass balance studies could not be performed to determine the primary elimination route. Clearance could not be calculated based on rifilgrastim plasma concentrations, but relatively rapid clearance has been reported in rat intravenous pharmacokinetic studies. Rifigligrastim is predicted to be primarily cleared via the nasal cavity, followed by the gastrointestinal tract. Metabolism/Metabolites Based on an in vitro metabolism study using fresh human hepatocytes, rifilgrastim does not appear to undergo significant metabolism. Biological Half-Life Plasma elimination half-life could not be calculated based on rifilgrastim plasma concentrations, but relatively short half-life has been reported in rat intravenous pharmacokinetic studies.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
The concentration of rifilgrastim in human breast milk has not been measured. Due to limited absorption through the eye, ophthalmic rifilgrastim is not expected to have any adverse effects on breastfed infants. To significantly reduce the amount of medication entering breast milk after using eye drops, press the tear duct at the corner of the eye for at least 1 minute, then blot away any excess medication with absorbent tissue.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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Protein Binding
The human plasma protein binding rate of rifilgrastim is approximately 99%, regardless of concentration (50 to 1000 ng/mL). The binding rate with isolated human serum albumin was 95% to 98%, and the binding rate with human α1-acid glycoprotein was 31.6% to 51.1%.

[1]. Lifitegrast, a Novel Integrin Antagonist for Treatment of Dry Eye Disease. Ocul Surf. 2016 Apr;14(2):207-15.

[2]. Corneal inflammation is inhibited by the LFA-1 antagonist, lifitegrast (SAR 1118). J Ocul Pharmacol Ther. 2013 May;29(4):395-402.

[3]. Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin(STZ) model of diabetic retinopathy (DR). Invest Ophthalmol Vis Sci. 2010 Oct;51(10):5198-204.

Rifibrate is an N-acyl-L-α-amino acid formed by the condensation of the carboxyl group of N-[2-(1-benzofuran-6-carbonyl)]-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid with the amino group of 3-(methanesulfonyl)-L-phenylalanine. It is used to treat dry eye syndrome (keratoconjunctivitis sicca). It has anti-inflammatory and lymphocyte function-associated antigen-1 (LFA-1) antagonist effects. It is an L-phenylalanine derivative, a sulfone compound, an N-acyl-L-α-amino acid, an isoquinoline compound, and a 1-benzofuran compound. Rifibrate is an FDA-approved drug for the treatment of dry eye syndrome (keratoconjunctivitis sicca). It is a tetrahydroisoquinoline derivative and a lymphocyte function-associated antigen-1 (LFA-1) antagonist, discovered through a rationally designed process. This ophthalmic solution was approved for marketing in July 2016 under the brand name Xiidra. Studies have shown that it can protect the corneal surface, relieve dry eye symptoms, act rapidly, and is well-tolerated in both topical and systemic administration. Rifigrafine is a lymphocyte function-associated antigen-1 (LFA-1) antagonist. Rifigrafine's mechanism of action is as a lymphocyte function-associated antigen-1 (LFA-1) antagonist. Rifigrafine is a tetrahydroisoquinoline derivative and also a lymphocyte function-associated antigen-1 (LFA-1) antagonist, available as an ophthalmic solution for the treatment of dry eye syndrome (DED; keratoconjunctivitis sicca; dry eye syndrome). After ophthalmic administration, although the exact mechanism of action of rifigrafine in treating dry eye syndrome is not fully elucidated, rifigrafine targets and binds to integrin LFA-1 (a protein present on the surface of leukocytes). This prevents the interaction between LFA-1 and its ligand, intercellular adhesion molecule-1 (ICAM-1). Because ICAM-1 may be overexpressed in the corneal and conjunctival tissues of patients with dry eye syndrome, rifilgrastim's blockade of the LFA-1/ICAM-1 interaction may inhibit T cell adhesion to ICAM-1 and potentially disrupt the formation of immune synapses. This may inhibit T cell proliferation, activation, and migration in the corneal and conjunctival tissues, as well as the release of pro-inflammatory cytokines. This may help reduce inflammation, protect the corneal surface from inflammation-mediated damage, and alleviate the symptoms of dry eye syndrome.
See also: Rifilgrastim Sodium (its active ingredient).

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Drug Indications
For the treatment of signs and symptoms of dry eye syndrome (keratoconjunctivitis sicca).
FDA Label
Treatment of Dry Eye
Mechanism of Action
Rifagine binds to integrin lymphocyte function-associated antigen-1 (LFA-1), a protein present on the surface of leukocytes. Rifagine blocks the interaction between LFA-1 and its homologous ligand, intercellular adhesion molecule-1 (ICAM-1). In dry eye, ICAM-1 may be overexpressed in the corneal and conjunctival tissues. The LFA-1/ICAM-1 interaction promotes the formation of immune synapses, leading to T cell proliferation/activation and migration to target tissues. In vitro studies have shown that rifilgrastim inhibits the adhesion of T cells to ICAM-1 in human T cell lines and inhibits the secretion of inflammatory cytokines, inflammatory mediators, chemokines, TNF-α, and IL-1 from human peripheral blood mononuclear cells.

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Pharmacodynamics
Rifiglitazone improves symptoms and reduces ocular surface damage by interfering with ocular inflammatory circulation. Rifiglitazone is a lymphocyte function-associated antigen-1 (LFA-1) antagonist that, through direct competitive antagonism, sequentially inhibits T cell recruitment, activation, and release of pro-inflammatory cytokines associated with dry eye.

C₂₉H₂₄CL₂N₂O₇S

615.48

614.068

1025967-78-5

Lifitegrast sodium;1119276-80-0

11965427

White to off-white solid powder

1.5±0.1 g/cm3

811.9±65.0 °C at 760 mmHg

444.8±34.3 °C

0.0±3.1 mmHg at 25°C

1.661

1.54

2

7

7

41

1100

1

CS(=O)(=O)C1=CC=CC(=C1)C[C@@H](C(=O)O)NC(=O)C2=C(C=C3CN(CCC3=C2Cl)C(=O)C4=CC5=C(C=C4)C=CO5)Cl

JFOZKMSJYSPYLN-QHCPKHFHSA-N

InChI=1S/C29H24Cl2N2O7S/c1-41(38,39)20-4-2-3-16(11-20)12-23(29(36)37)32-27(34)25-22(30)13-19-15-33(9-7-21(19)26(25)31)28(35)18-6-5-17-8-10-40-24(17)14-18/h2-6,8,10-11,13-14,23H,7,9,12,15H2,1H3,(H,32,34)(H,36,37)/t23-/m0/s1

(2S)-2-[[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-3,4-dihydro-1H-isoquinoline-6-carbonyl]amino]-3-(3-methylsulfonylphenyl)propanoic acid

SAR 1118 SAR 1118-023SAR-1118SHP-606SAR1118-02SHP606SAR 1118SHP 606SAR1118Lifitegrast sodium SAR-1118-023 Xiidra

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 29 mg/mL (~47.12 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (3.38 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)