June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Preclinical examination of the toxicity and toxicokinetics of oxymetazoline HCl ophthalmic solution, 0.1% in rabbits
Author Affiliations & Notes
  • Matthew S. Cowlen
    Cowlen Consulting, LLC, Chapel Hill, North Carolina, United States
  • Martin Bussieres
    V&O Services, Inc., Kirkland, Quebec, Canada
  • Ellis Loew
    Cornell University, Ithaca, New York, United States
  • Herlind Biedert
    Nuvisan, GmbH, Neu-Ulm, Germany
  • Tina deVries
    Vertical Pharmaceuticals, LLC, Bridgewater, New Jersey, United States
  • Footnotes
    Commercial Relationships   Matthew Cowlen, Osmotica Pharmaceutical US LLC, the parent company of Vertical Pharmaceuticals, LLC (C); Martin Bussieres, Osmotica Pharmaceutical US LLC, the parent company of Vertical Pharmaceuticals, LLC (C); Ellis Loew, Osmotica Pharmaceutical US LLC, the parent company of Vertical Pharmaceuticals, LLC (C); Herlind Biedert, Osmotica Pharmaceutical US LLC, the parent company of Vertical Pharmaceuticals, LLC (C); Tina deVries, Osmotica Pharmaceutical US LLC, the parent company of Vertical Pharmaceuticals, LLC (E), Osmotica Pharmaceutical US LLC, the parent company of Vertical Pharmaceuticals, LLC (I)
  • Footnotes
    Support  Study was supported by Osmotica Pharmaceutical US LLC
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2969. doi:
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      Matthew S. Cowlen, Martin Bussieres, Ellis Loew, Herlind Biedert, Tina deVries; Preclinical examination of the toxicity and toxicokinetics of oxymetazoline HCl ophthalmic solution, 0.1% in rabbits. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2969.

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

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Abstract

Purpose : RVL-1201 (oxymetazoline hydrochloride ophthalmic solution, 0.1%) is a topical investigational drug developed for the treatment of acquired blepharoptosis (ptosis, or droopy eyelid). The aim of this study was to determine the ocular and systemic toxicity and toxicokinetics of RVL-1201 in rabbits.

Methods : RVL-1201 or vehicle was administered two or three times (2x or 3x) daily onto the corneal surface of both eyes of New Zealand white rabbits for 26 weeks, followed by a 4-week recovery period. Three groups of rabbits were dosed: Group 1 received vehicle 3x daily, Group 2 received RVL-1201 2x daily (0.14 mg/animal/day), and Group 3 received RVL-1201 3x daily (0.21 mg/animal/day). Each group included 10 male and 10 female rabbits during the main study, and 5 male and 5 female rabbits during the recovery period. Evaluations included clinical signs, body weight, food consumption, ophthalmic examinations (slit lamp biomicroscopy and indirect ophthalmoscopy), tonometry, electroretinography (ERG), clinical pathology (hematology, clinical chemistry, coagulation), toxicokinetics, organ weights, and histopathology of ocular and systemic tissues. Oxymetazoline plasma concentration was determined using a validated LC-MS/MS method.

Results : There were no RVL-1201-related deaths, adverse clinical signs, or changes in body weight, food consumption, tonometry or ERG parameters, posterior ophthalmic exam findings, clinical pathology, organ weights, or histopathology. Dose-related anterior chamber fibrin (ACF), mostly very slight, was observed via slit lamp in 8/60 rabbits only when examinations were conducted shortly after ERG. ACF was transient, was not associated with an inflammatory response, and was not considered adverse. ACF was not observed in RVL-1201 human trials. Systemic exposure to oxymetazoline was very low (Cmax range: 1-2 ng/mL; AUC range: 4-15 ng●h/mL), with no sex-related differences between males and females. Slight accumulation of oxymetazoline in plasma was noted in high-dose females on Day 182 vs Day 1. The no-observed adverse effect level (NOAEL) of RVL-1201 was 0.21 mg/animal/day (0.1% oxymetazoline, 3x daily to both eyes).

Conclusions : Topical ocular administration of RVL-1201 to rabbits 2x or 3x daily for 26 weeks was generally well tolerated, with no systemic toxicity, RVL-1201-related histopathological findings, or any clinically relevant or adverse ocular effects.

This is a 2020 ARVO Annual Meeting abstract.

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