Ocular Distribution and Pharmacokinetics of Lifitegrast in Pigmented Rabbits and Mass Balance in Beagle Dogs

Purpose: 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 (14)C-lifitegrast mass balance/excretion in dogs. Methods: Female pigmented rabbits received a single topical o...

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Detalles Bibliográficos
Autores principales: Chung, Jou-Ku, Spencer, Elizabeth, Hunt, Matthew, McCauley, Thomas, Welty, Devin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Mary Ann Liebert, Inc., publishers 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963635/
https://www.ncbi.nlm.nih.gov/pubmed/29267138
http://dx.doi.org/10.1089/jop.2017.0106
Descripción
Sumario:Purpose: 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 (14)C-lifitegrast mass balance/excretion in dogs. Methods: 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 (14)C-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 (C(max)), time to C(max) (t(max)), and area under the concentration-time curve from 0 to 8 h (AUC(0–8)). Results: In rabbits, lifitegrast C(max) and AUC(0–8) were similar between formulations. C(max) 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). AUC(0–8) followed a similar trend. Plasma concentrations were low (C(max) <18 ng/mL). Tissue/plasma t(max) was ∼0.25–1 h. In dogs, after intravenous/ocular doses, (14)C-lifitegrast was eliminated primarily through feces. Excreted radioactivity was mainly unchanged lifitegrast. Conclusions: 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 (14)C-lifitegrast suggests minimal drug metabolism in vivo. This is consistent with lifitegrast clinical trial efficacy/safety data.