Purchase this article with an account.
Adam Brockman, David Albers, William K McVicar; Safety and tolerability of trabodenoson and latanoprost in dogs following a 39 week ocular (topical) instillation. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5168. doi: https://doi.org/.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
To determine ocular toxicity of 3% and 6% trabodenoson alone or in the presence of latanoprost when administered twice daily in one eye for 39 weeks in beagle dogs.
Topical ocular formulations of trabodenoson (TRABO - 3%: 1500 µg/dose; 6%: 3000 µg /dose) were administered twice daily alone or in combination with once daily latanoprost (LAT) (0.005%: 1.5 µg/dose) for 39 weeks in the right eye of beagle dogs (8-9 month old: 3 males and 3 females per treatment group. Animals were monitored daily, with several in-life procedures conducted, including ophthalmoscopic examinations, slit-lamp biomicroscopy and Hackett-McDonald scoring on all animals pretest, monthly, and at the end of study. Electrocardiography (ECG) examinations were performed twice monthly two hours after the first daily dose. Blood was collected on days 1, 28, and 273, and plasma was analyzed for TRABO and its primary metabolite using validated bioanalytical methods. Toxicokinetic (TK) parameters were estimated using a non-compartmental approach consistent with an ocular route of administration. A complete necropsy was performed and representative tissues from all organ systems were preserved for histopathological evaluation.
No dose-related clinical signs or changes in body weight, ECG, calculated heart rate were noted. No TRABO-related findings were noted from external or internal ocular examinations. Pupillary constriction and hyperemia were noted in LAT-treated animals only. TK evaluation estimated maximum plasma concentration of TRABO was reached within the first 15-60 min post dose when dosed alone or in combination with LAT; AUC0-8hr and Cmax increased with increasing dose in a less than dose proportional manner. No organ weight or gross pathological findings were noted in any of the treatment groups. No histopathological findings were noted in any ocular tissue with TRABO alone or in combination w LAT, and any microscopic findings in other tissues were considered incidental and unrelated.
TRABO given by twice daily ocular instillation for 39 weeks at 1500 or 3000 µg/dose with or without once daily 1.5 µg/dose LAT to beagle dogs was well-tolerated and produced no evidence of ocular or systemic toxicity. Based on these results, the no-observed-adverse-effect level for TRABO was considered to be 603-655 µg/kg/day alone, or in combination with 0.15-0.163 µg/kg/day LAT.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
This PDF is available to Subscribers Only