Safety and Pharmacokinetics of a Novel Lymphocyte Function-associated Antigen-1 Antagonist Ophthalmic Solution (SAR 1118) in Healthy Adults

Semba, Charles P.; Swearingen, Dennis; Smith, Valerie; Newman, Mary S.; O’Neill, Charles; Burnier, John; Haughey, David B.; Gadek, Thomas R.

doi:10.1089/jop.2009.0105

Cited by 31 publications

(27 citation statements)

References 8 publications

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“…57 Lifitegrast, an LFA-1 antagonist, is the first agent targeting LFA-1/ICAM-1 to be approved for the topical treatment of DED. 36,58,59 …”

Section: Targeting Lfa-1/icam-1 Interaction In Dedmentioning

confidence: 99%

“…58 Following ophthalmic administration of lifitegrast in humans, it is cleared rapidly from the systemic circulation; however, it is transiently present in the plasma (peak plasma concentration in humans is detected within 5 min). 59 Therefore, in the efferent arm, lifitegrast also may inhibit activated T cells from exiting from the conjunctival blood vessels into the ocular surface tissues. Further studies are needed to test these theories as the exact mechanism and sites of action of lifitegrast have not yet been confirmed.…”

Section: Targeting Lfa-1/icam-1 Interaction In Dedmentioning

confidence: 99%

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LFA-1/ICAM-1 Interaction as a Therapeutic Target in Dry Eye Disease

Pflugfelder

Stern

Zhang

et al. 2017

Journal of Ocular Pharmacology and Therapeutics

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Dry eye disease (DED) is a common ocular disorder associated with inflammation of the lacrimal gland and ocular surface. The interaction of the integrin lymphocyte function-associated antigen-1 (LFA-1) with its cognate ligand intercellular adhesion molecule-1 (ICAM-1) is known to have important roles in the interaction of a variety of cells involved in immune responses and inflammation, including those prominent in ocular surface inflammation. Lifitegrast, an LFA-1 antagonist that blocks binding of ICAM-1 to LFA-1, has recently been approved in the United States for the treatment of signs and symptoms of DED. In this review, we evaluate research findings to explore the potential role of LFA-1/ICAM-1 interaction in the pathophysiology of DED, and the evidence supporting LFA-1/ICAM-1 interaction as a rational therapeutic target in DED. The results of our review suggest that LFA-1/ICAM-1 interaction may play important roles in the cell-mediated immune response and inflammation associated with DED, including facilitating the homing of dendritic cells to the lymph nodes, interaction of dendritic cells with T cells and subsequent T cell activation/differentiation, migration of activated CD4+ T cells from the lymph nodes to the ocular surface, reactivation of T cells by resident antigen-presenting cells at the ocular surface, and recruitment and retention of LFA-1-expressing T cells in the conjunctival epithelium. Based on the available evidence, inhibition of LFA-1/ICAM-1 interaction represents a rational targeted approach in treating DED. Notably, inhibition of LFA-1/ICAM-1 binding with lifitegrast offers a novel approach to reducing ocular surface inflammation in this condition.

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“…57 Lifitegrast, an LFA-1 antagonist, is the first agent targeting LFA-1/ICAM-1 to be approved for the topical treatment of DED. 36,58,59 …”

Section: Targeting Lfa-1/icam-1 Interaction In Dedmentioning

confidence: 99%

Section: Targeting Lfa-1/icam-1 Interaction In Dedmentioning

confidence: 99%

LFA-1/ICAM-1 Interaction as a Therapeutic Target in Dry Eye Disease

Pflugfelder

Stern

Zhang

et al. 2017

Journal of Ocular Pharmacology and Therapeutics

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“…In participants administered lifitegrast twice daily for 10 days, a maximum tear fluid lifitegrast concentration (91,413 ng/mL) was achieved in a median time of 0.3 h, and there was no evidence of lifitegrast accumulation in tears during repeated ocular dosing. In the same study, low levels of lifitegrast in the plasma were detected within 5 min of instillation and were cleared from the plasma within 1-4 h. The C max of lifitegrast following ocular administration was <5 nM (<3 ng/mL) and there was no indication of systemic accumulation with repeated ocular dosing [17,27]. In the SONATA (Safety Of a 5.0% coNcentrATion of lifitegrAst ophthalmic solution) 1-year safety trial [28], plasma concentrations of lifitegrast were low, and there was no accumulation in plasma over time (mean concentration of lifitegrast in plasma was below the lower limit of quantification [0.5 ng/mL] at days 0, 180, and 360).…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 87%

“…In a phase 1 trial [27], twice-daily administration of lifitegrast ophthalmic solution 5.0% to healthy volunteers resulted in a tear fluid lifitegrast concentration that exceeded the target therapeutic level in the eye of >1 μM (~600 ng/mL), i.e. substantially higher than the IC 50 and EC 50 values demonstrated in vitro for LFA-1/ICAM-1 binding and cytokine inhibition, respectively (Section 3.2).…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

Lifitegrast for the treatment of dry eye disease in adults

Donnenfeld

Perry

Nattis

et al. 2017

Expert Opinion on Pharmacotherapy

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Dry eye disease (DED) is a common ocular disorder that can have a substantial burden on quality of life and daily activities. Lifitegrast ophthalmic solution 5.0% is the first medication approved in the US for the treatment of the signs and symptoms of DED. The aim of this article is to summarize the preclinical and clinical data on lifitegrast and discuss how lifitegrast may fit into the current treatment landscape for DED. Areas covered: A literature search of published preclinical and clinical data was conducted to review the chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy/safety of lifitegrast. The impact that lifitegrast may have on DED treatment practices is also discussed. Expert opinion: The introduction of lifitegrast provides a potentially important additional option for eye care professionals treating DED. In clinical trials conducted in adults with DED, lifitegrast ophthalmic solution 5.0% improved both signs and symptoms of DED. Of note, in 2 phase 3 trials, symptom improvements were observed as early as 2 weeks, which may be explained by lifitegrast's unique mechanism of action of blocking a specific signaling pathway in inflammation. Future research should include evaluation of whether lifitegrast can be used in combination with other DED treatments.

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“…In animal models of diabetes, topical administration of this drug has been shown to reach the retina and decrease leukostasis and breakdown of the BRB 66. Topical administration has been shown to be well tolerated in phase I trials 67. Further investigation is needed to determine if SAR 1118 or other ICAM-1 or LFA-1 inhibitors will be safe and effective for the treatment of DME.…”

Section: Additional Targets and Emerging Therapiesmentioning

confidence: 99%

Diabetic macular edema: Current and emerging therapies

Wenick

Bressler

2012

Middle East Afr J Ophthalmol

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Diabetic macular edema is a leading cause of vision impairment among people within the working- age population. This review discusses the pathogenesis of diabetic macular edema and the treatment options currently available for the treatment of diabetic macular edema, including for focal/grid photocoagulation, intravitreal corticosteroids and intravitreal anti-vascular endothelial growth factor agents. The biologic rationale for novel therapeutic agents, many of which are currently being evaluated in clinical trials, also is reviewed.

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Safety and Pharmacokinetics of a Novel Lymphocyte Function-associated Antigen-1 Antagonist Ophthalmic Solution (SAR 1118) in Healthy Adults

Abstract: SAR 1118 Ophthalmic Solution appears safe and well-tolerated up to 5.0% TID in healthy adult subjects. PK analysis shows adequate ocular exposure with minimal systemic exposure.

Cited by 31 publications

References 8 publications

LFA-1/ICAM-1 Interaction as a Therapeutic Target in Dry Eye Disease

LFA-1/ICAM-1 Interaction as a Therapeutic Target in Dry Eye Disease

Lifitegrast for the treatment of dry eye disease in adults

Diabetic macular edema: Current and emerging therapies

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