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Cadmus Rich, David S Albers, Robin Guy, William K McVicar; Safety and tolerability of trabodenoson in non-human primates following a 4 week ocular (topical) instillation. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5716.
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© ARVO (1962-2015); The Authors (2016-present)
To determine ocular toxicity of 3% and 6% trabodenoson when administered twice-daily in one eye for four weeks in cynomolgus monkeys.
Topical ocular formulations of trabodenoson (3%: 255 µg/dose; 6%: 510 µg/dose) were administered twice daily for 28 days in the right eye of cynomolgus monkeys (approximately 3 y.o.; half male/half female per dose group; vehicle, n=2; 3%, n=4; 6%, n=4). Animals were monitored daily and several in-life procedures were conducted, including external ocular examinations using a modified Draize scoring scale (pre, then twice weekly), and internal funduscopic and biomicroscopic/slit-lamp examinations following mydriatic administration (pre, days 3, 8, 26). Electrocardiography (ECG) recordings were performed 30 min post AM dose (pre, days 2 and 27) and prior to AM dose on days 3 and 28. Heart rates were recorded 0.5 and 8 hr post AM dose (pre, days 1, 9, 15, 22). Blood was collected by venipuncture on days 1 and 28, and plasma was analyzed for trabodenoson 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 at the end and representative tissues from all organ systems, including all ocular tissues, were harvested and preserved for histopathological evaluation.
No clinical signs or changes in body weight, temperature, food intake, ECG recordings, or heart rate were noted in any of the treatment groups. No remarkable changes were noted from external or internal ocular examinations. TK evaluation estimated maximum plasma concentration of trabodenoson was reached within the first 30 min post dose with estimated half-life between 0.5-3 hours. 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 either dose of trabodenoson, and any microscopic findings in other tissues were considered incidental and unrelated.
Trabodenoson given by twice-daily ocular instillation for 4 weeks in a 3% or 6% ocular formulation to cynomolgus monkeys was well-tolerated and produced no evidence of ocular or systemic toxicity. Based on these results, the no-observed-adverse-effect level was considered to be 276-358 µg/kg/day.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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