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- Title
Ocular Distribution and Pharmacokinetics of Lifitegrast in Pigmented Rabbits and Mass Balance in Beagle Dogs.
- Authors
Chung, Jou-Ku; Spencer, Elizabeth; Hunt, Matthew; McCauley, Thomas; Welty, Devin
- Abstract
<bold>Purpose: </bold>Lifitegrast is approved in the United States for the treatment of dry eye disease (DED). We assessed lifitegrast's ocular distribution/pharmacokinetic profile in rabbits, and 14C-lifitegrast mass balance/excretion in dogs.<bold>Methods: </bold>Female pigmented rabbits received a single topical ocular dose of lifitegrast (Formulation No. 1, n = 25; No. 2, n = 25) per eye twice daily (target, 1.75 mg/eye/dose). Blood/ocular tissues were collected on day 5. Beagle dogs received single intravenous (n = 10; target, 3 mg, 262 μCi/animal) and ocular (n = 8, target, 3 mg, 30 μCi/eye) doses of 14C-lifitegrast (∼8 weeks between doses). Blood, excreta, and cage rinse/wipes were collected. Concentrations were measured by mass spectrometry/liquid scintillation counting. Pharmacokinetic analyses (noncompartmental) included maximum concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve from 0 to 8 h (AUC0-8).<bold>Results: </bold>In rabbits, lifitegrast Cmax and AUC0-8 were similar between formulations. Cmax was highest in ocular anterior segment tissues: 5,190-14,200 ng/g [conjunctiva (palpebral/bulbar), cornea, anterior sclera]. Posterior segment tissues had lower concentrations (0-826 ng/g). AUC0-8 followed a similar trend. Plasma concentrations were low (Cmax <18 ng/mL). Tissue/plasma tmax was ∼0.25-1 h. In dogs, after intravenous/ocular doses, 14C-lifitegrast was eliminated primarily through feces. Excreted radioactivity was mainly unchanged lifitegrast.<bold>Conclusions: </bold>High exposure of lifitegrast in rabbit ocular anterior segment tissues and low exposure in posterior segment tissues/plasma suggests that lifitegrast reaches target tissues for DED treatment, with low potential for off-target systemic/ocular effects. Excretion of unchanged 14C-lifitegrast suggests minimal drug metabolism in vivo. This is consistent with lifitegrast clinical trial efficacy/safety data.
- Subjects
TREATMENT of dry eye syndromes; BEAGLE (Dog breed); RABBITS; DRUG dosage; MASS spectrometry; ANIMAL experimentation; COMPARATIVE studies; CORNEA; DOGS; DRY eye syndromes; RESEARCH methodology; MEDICAL cooperation; OPHTHALMIC drugs; PHENYLALANINE; RESEARCH; SULFONES; CUTANEOUS therapeutics; EVALUATION research
- Publication
Journal of Ocular Pharmacology & Therapeutics, 2018, Vol 34, Issue 1/2, p224
- ISSN
1080-7683
- Publication type
journal article
- DOI
10.1089/jop.2017.0106