Lifitegrast

Biological Activity

In vitro: Lifitegrast is a novel small molecule integrin antagonist that inhibits T cell-mediated inflammation by blocking the binding of two important cell surface proteins (lymphocyte function-associated antigen 1 and intercellular adhesion molecule 1), thus lessening overall inflammatory responses. Lifitegrast strongly inhibits Jurkat T cell attachment to ICAM-1 with an IC50 of 2.98 nM. In vivo: Lifitegrast, has potent anti-inflammatory activity on corneal inflammation induced by antibiotic-killed P. aeruginosa and S. aureus in the presence of a silicone hydrogel lens with the optimal application being a 1% solution applied either 2 or 3 times prior. Topical application of lifitegrast to the corneal surface of healthy adults is safe and well tolerated. SAR 1118 ophthalmic drops administered thrice daily deliver therapeutic levels of SAR 1118 in the retina and can alleviate the retinal complications associated with diabetes.

Protocol

Cell Experiment
Cell lines	T-cell
Preparation method	Lifitegrast potently inhibits human T-cell binding to human ICAM-1, T-cell activation and cytokine release, and formation of the immunologic synapse.
Concentrations	3 nM
Incubation time

Animal Experiment
Animal models	dogs diagnosed with keratoconjunctivitis sicca
Formulation
Dosages
Administration	i.v.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

References

Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease.
Semba CP, et al. Clin Ophthalmol. 2016 Jun 10;10:1083-94. PMID: 27354762.

Lifitegrast Ophthalmic Solution 5.0% versus Placebo for Treatment of Dry Eye Disease: Results of the Randomized Phase III OPUS-2 Study.
Tauber J, et al. Ophthalmology. 2015 Dec;122(12):2423-31. PMID: 26365210.