RESUMO
The purpose of this study was to evaluate the potential irritating effects and the systemic exposure level of an antibacterial ointment containing REP8839 as a single agent or in combination with mupirocin versus Bactroban Nasal in rabbits. Additionally, the reversibility of REP8839 effects during a 14-day recovery period was assessed. Five treatment groups of six male and six female New Zealand White rabbits received dose levels of 1%, 2%, and 4% REP8839, 2% Bactroban Nasal, or 2% REP8839/2% mupirocin combination. One additional group of six animals/sex served as the control and received the vehicle, Petrolatum/Softisan 649. The test article or vehicle was administered to all groups via topical administration to the external nares, twice a day (approx. 8h intervals between the doses) for 21 consecutive days, at a dose volume of 100 microL per nare/dose for a total of 400 microL per day (200 microL per nare). Two animals/sex/group were maintained for a 14-day recovery period. The external nares were reflected back and the mucosal lining was evaluated and scored for erythema and edema within 30-60 min following the first dose each day. Blood samples were collected from all animals at designated time points on Day 21 of the study to assess systemic exposure levels. Cross-sectioning of the nasal tract was conducted in all the groups for microscopic evaluation. Mucosal scoring of the nares did not reveal any edema or erythema in any of the dose groups with the antibacterial alone, with the combination product, or with Bactroban Nasal. Mean body weights and food consumption were not adversely impacted by the test articles. Minimal plasma exposure was observed in the rabbits (<5 ng/mL). The REP8839 groups did appear to have dose-responsive exposure (from below the limit of quantitation to 5 ng/mL with 1%, 2%, and 4% REP8839, respectively). Microscopic changes on the nasal sectioning noted in these animals were infrequent and considered incidental findings unrelated to administration of the test articles. In conclusion doses of up to 4% of REP8839 ointment as a single agent or 2% in the combination product, as well as 2% Bactroban Nasal, were not found to induce mucosal irritation when applied topically to the external nares twice a day for 21 consecutive days. Additionally, no delayed effects were observed in the recovery animals.