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John H Ansede, William Thelin, Richard C Boucher, M. Ross Johnson, Pramod Terse, Katherine Warren, Jose L Boyer; Ocular Pharmacokinetics of P-321, a Novel Long-Acting Epithelial Sodium Channel Blocker. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3693.
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P-321 is a potent epithelial sodium channel (ENaC) blocker that is being developed by Parion Sciences as a topical therapy for the treatment of dry eye. ENaC plays a key role in the regulation of tear fluid and is therefore an attractive target for the treatment of dry eye. To study the pharmacokinetics of P-321 in the eye, P-321 was administered via ocular instillation and drug concentrations in ocular tissues were measured following a single dose or during repeated administration over 14-days.
P-321 (0.1%) was administered via ocular instillation to Dutch Belted rabbits. Drug levels were measured in plasma, tears, and ocular tissues following a single administration and at different times during QID administration for 14 days. Following extraction, the concentration of P-321 was assayed by LC-MS/MS.
P-321 is metabolically stable and therefore only the parent drug was monitored. Following single administration, P-321 elimination from tears was biphasic showing a rapid initial loss from tears followed by a long terminal elimination phase (t1/2 = 24 hr). Upon repeated administration, tear concentrations of P-321 increased and reached steady state levels by Day 6. P-321 was retained in the conjunctiva following single dose administration with palpebral drug concentration approximately five times higher than bulbar conjunctiva. After a single dose, conjunctiva concentrations of P-321 remained relatively constant for up to 48 hours and steady-state levels were achieved by Day 2 during 14 days of QID dosing. P-321 was only detected at sub nanomolar concentrations in aqueous humor five minutes post-dose. Aqueous humor concentrations increased slightly during multiple dose administration reaching steady state levels by Day 4. P-321 was detected in the cornea immediately following dose administration, however, no drug was detected thereafter or during 14-days of QID administration. P-321 was not detected in retina or lacrimal glands.
P-321 is a novel ocular hydrating agent capable of restoring normal tear volume in a dry eye animal model. The results presented in this study indicate that P-321 is well retained on the ocular surface of the eye (primarily in the tears and conjunctiva), providing the pharmacokinetic basis to explain its long duration of action. Furthermore, P-321 shows very little penetration or accumulation in other ocular tissues.
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