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William K McVicar, Norman Kim, David S Albers; Tolerability and bioavailability of trabodenoson following local dermal administration in minipigs. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5033.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the dermal tolerance and bioavailability of trabodenoson following dermal administration in minipigs.
On day one, four female minipigs (3-4 months; 9-9.8 kg) received a dermal administration of 10 mg of trabodenoson formulated in a 2-hydroxypropyl-β-cyclodextrin (HPCD) solution (10 mg/ml) on the dorsal surface. The application sites were wiped/washed clean after 10 minutes. Dermal tolerability was evaluated by a modified Draize scoring method at pre-dose, 15 min, 1 and 4 hours (hr) post-dose. On day 2, the same animals received a dermal administration of 25 mg trabodenoson formulated in an ophthalmic suspension (25 mg/ml) to the same dorsal sites. The application sites were wiped/washed clean after 1 hr. Sites were again evaluated by the modified Draize scoring method at pre-dose, 15 min, 1 and 4 hrs post-dose. Additionally, blood samples were collected from the cranial vena cava prior to dosing and at 5, 15, 30 min, 1, 4, 8 hrs after dosing. On day 3, animals received an IV administration of trabodenoson (0.2 mg/kg in HPCD solution) and blood samples were collected prior to dosing and at 5, 15, 30 min, 1, 4, 8 hrs after dosing. Plasma concentrations of trabodenoson and its primary metabolite, INO-2446, were measured using validated bioanalytical methods.
There were no signs of erythema, edema, eschar, blanching, fissuring or ulceration observed on day 1 or day 2 following dermal administration of trabodenoson solution or suspension. Plasma concentrations of trabodenoson following dermal exposure were generally low and variable: mean Cmax was 115 pg/ml and mean AUC0-t was 464 pg.hr/ml. Plasma concentrations of INO-2446 were BLQ (ie, <10 pg/ml). Following IV administration of trabodenoson, mean trabodenoson Cmax was 125,000 pg/ml and the mean AUC0-t was 107,686 pg.hr/ml; mean INO-2446 Cmax was 2688 pg/ml and the mean AUC0-t was 4324 pg.hr/ml.
Dermal application of trabodenoson in an ophthalmic suspension up to 25 mg/site for up to 60 minutes, or in a HPCD solution at 10 mg/site for up to 10 minutes, was non-irritating on the skin. The absolute bioavailability of trabodenoson following dermal administration was very low (0.0215%), indicating a low likelihood of systemic exposure after dermal contact following ocular dosing.
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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