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 1.70ng/mL was reached within 15 minutes of application. Quantifiable trough plasma concentrations ranged from 0.55 ng/mL to 3.74 ng/mL. Observations show limited systemic exposure that produces significant clinical outcomes.
Not possible to perform mass balance study to determine the main route of elimination.
Not possible to calculate clearance rate based on plasma concentrations of lifitegrast, but reported to be relatively fast in rat I.V. pharmacokinetics study. It is predicted that lifitegrast is cleared via nasal and subsequently gastrointestinal tract.

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Metabolism / Metabolites
Based on the findings of an in vitro metabolism study using fresh human hepatocytes, lifitegrast does not appear to undergo significant metabolism.

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Biological Half-Life
Not possible to calculate plasma elimination half-life based on plasma concentrations of lifitegrast, but reported to be relatively short in rat I.V. pharmacokinetics study.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Breastmilk levels of lifitegrast have not been measured in humans. Because absorption from the eye is limited, ophthalmic lifitegrast would not be expected to cause any adverse effects in breastfed infants. To substantially diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Human plasma protein binding of lifitegrast was approximately 99%, independent of concentration (50 to 1000ng/mL). Binding to isolated human serum albumin was 95% to 98%, and 31.6% to 51.1% to human α1-acid glycoprotein.

[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.

Lifitegrast is an N-acyl-L-alpha-amino acid obtained by formal condensation of the carboxy 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. Used for treatment of keratoconjunctivitis sicca (dry eye syndrome). It has a role as an anti-inflammatory drug and a lymphocyte function-associated antigen-1 antagonist. It is a L-phenylalanine derivative, a sulfone, a N-acyl-L-alpha-amino acid, a member of isoquinolines and a member of 1-benzofurans.
Lifitegrast is a FDA approved drug for the treatment of keratoconjunctivitis sicca (dry eye syndrome). It is a tetrahydroisoquinoline derivative and lymphocyte function-associated antigen-1 ( LFA-1) antagonist that was discovered through the rational design process. The ophthalmic solution was approved in July, 2016 under the trade name Xiidra. It has shown to protect the corneal surface and alleviate the symptoms of dry eye syndrome with fast onset of action and well tolerated profile in both local and systemic setting.
Lifitegrast is a Lymphocyte Function-Associated Antigen-1 Antagonist. The mechanism of action of lifitegrast is as a Lymphocyte Function-Associated Antigen-1 Antagonist.
Lifitegrast is a tetrahydroisoquinoline derivative and lymphocyte function-associated antigen-1 (LFA-1) antagonist, that can be used as an ophthalmic solution for the treatment of dry eye disease (DED; keratoconjunctivitis sicca; dry eye syndrome). Upon ocular administration and although the exact mechanism of action of lifitegrast in DED is not fully known, lifitegrast targets and binds to the integrin LFA-1, a cell surface protein found on leukocytes. This prevents the interaction of LFA-1 with its cognate ligand intercellular adhesion molecule-1 (ICAM-1). As ICAM-1 may be overexpressed in corneal and conjunctival tissues in DED, the blockage of the LFA-1/ICAM-1 interaction by lifitegrast may inhibit T-cell adhesion to ICAM-1 and may abrogate the formation of an immunological synapse. This may prevent T-cell proliferation, activation and migration and the release of pro-inflammatory cytokines in the corneal and conjunctival tissues. This may reduce inflammation, protect the corneal surface from inflammatory-mediated damage and reduce the symptoms of DED.
See also: Lifitegrast Sodium (is active moiety of).

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Drug Indication
For the treatment of signs and symptoms of keratoconjunctivitis sicca (dry eye syndrome).
FDA Label
Treatment of dry eye disease

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Mechanism of Action
Lifitegrast 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 proliferation/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, inflammatory mediators, chemokines, TNF-α, and IL-1 in human peripheral blood mononuclear cells.

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Pharmacodynamics
Lifitegrast addresses both the symptoms and the resulting ocular surface damage by interfering with ocular inflammatory cycle. Lifitegrast is a lymphocyte function–associated antigen-1 antagonist through direct competitive antagonism and sequentially inhibits the T-cell recruitment, activation, and proinflammatory cytokine release associated with dry eye syndrome.

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.)