June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Ocular distribution and pharmacokinetics of lifitegrast following repeat topical ocular dose administration to pigmented rabbits
Author Affiliations & Notes
  • Jou-Ku Chung
    Drug Metabolism and Pharmacokinetics, Shire, Lexington, Massachusetts, United States
  • Elizabeth Spencer
    Drug Metabolism, Covance Laboratories Inc., Madison, Wisconsin, United States
  • Matthew Hunt
    Drug Metabolism, Covance Laboratories Inc., Madison, Wisconsin, United States
  • Devin Welty
    Drug Metabolism and Pharmacokinetics, Shire, Lexington, Massachusetts, United States
  • Thomas McCauley
    Research and Development, Shire, Lexington, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Jou-Ku Chung, Shire PLC (E), Shire PLC (I); Elizabeth Spencer, Covance Laboratories Inc. (E), Shire PLC (C); Matthew Hunt, Covance Laboratories Inc. (E), Shire PLC (C); Devin Welty, Shire PLC (E), Shire PLC (I); Thomas McCauley , Shire PLC (E), Shire PLC (I)
  • Footnotes
    Support  Shire Development LLC
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 449. doi:
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      Jou-Ku Chung, Elizabeth Spencer, Matthew Hunt, Devin Welty, Thomas McCauley; Ocular distribution and pharmacokinetics of lifitegrast following repeat topical ocular dose administration to pigmented rabbits. Invest. Ophthalmol. Vis. Sci. 2017;58(8):449.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To assess ocular distribution and pharmacokinetics (PK) after repeat topical ocular administration of two Phase 3 formulations of lifitegrast in pigmented rabbits. Lifitegrast is a lymphocyte function-associated antigen-1 (LFA-1) antagonist recently approved in the US for treatment of signs and symptoms of dry eye disease (DED).

Methods : Female pigmented rabbits received a single topical ocular dose of lifitegrast (formulation #1, n=25; #2, n=25) in each eye, twice daily for 4 days and once on day 5, at a target dose level of 1.75 mg/eye/dose. Animals were euthanized on day 5; blood and ocular tissues were collected from 5 animals per formulation per time point at 0.25, 0.5, 1, 3, and 8 h after last dose. Liquid chromatography tandem mass spectrometry was used to measure lifitegrast concentrations. PK analyses (non-compartmental) included determination of maximum concentration (Cmax), time to maximum concentration (tmax), and area under concentration-time curve from 0 to 8 h (AUC0-8).

Results : Cmax and AUC0-8 for ocular tissues and plasma were similar between the formulations. Lifitegrast concentrations were highest in the ocular anterior segment tissues, with Cmax for the conjunctiva (palpebral and bulbar), cornea, and sclera (anterior) in the range 5190–14200 ng/g. Concentrations were lower in other ocular tissues, with the next highest Cmax 826 ng/g for the sclera (posterior). Very low/non-detectable lifitegrast concentrations (0–36.0 ng/g) were observed in the lens, optic nerve, retina and vitreous humor. Across all tissues, tmax was ~0.25–1 h, indicating rapid absorption after administration. Overall exposure (AUC0-8) for both formulations was highest in the conjunctiva (palpebral), followed by the cornea, sclera (anterior), conjunctiva (bulbar), sclera (posterior), iris-ciliary body, aqueous humor, and choroid-retinal pigmented epithelium. The plasma had low lifitegrast concentrations (Cmax: formulation #1, 17.4 ng/mL; #2, 9.52 ng/mL), and tmax (#1 and #2, 0.25 h).

Conclusions : The high exposure of lifitegrast in rabbit ocular anterior segment tissues, and low exposure in posterior segment tissues and plasma, suggests that lifitegrast is likely to reach the target tissues for DED treatment while having low potential for off-target systemic or ocular effects. The PK profile of lifitegrast was similar between formulations.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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