Abstract
Purpose :
The neuroprotective effect of brimonidine may result in it being an effective treatment for geographic atrophy (GA), an advanced form of AMD. Additionally, intravitreal administration of brimonidine will be able to achieve sustained pharmacologically effective concentrations in the retina. Duration of drug release and posterior segment pharmacokinetics was evaluated in rabbits and monkeys following intravitreal administration of brimonidine drug delivery system (Brimo DDS). Based on this data, modeling and simulation was used to guide dosing frequency in the clinical study.
Methods :
New Zealand White rabbits and Cynomolgus monkeys (2-3 animals/timepoint) received a single bilateral intravitreal injection of 400 µg of Brimo DDS. The pharmacokinetics of Brimo DDS was evaluated over a period of 6 months in rabbits and 5 months in monkeys. In monkeys, implant degradation was tracked up to 9 months. At designated timepoints, blood, aqueous humor (AH) , retina (R) and vitreous (V) were collected. For retina, an 8mm circular punch was taken over the visual streak and macula in rabbits and monkeys, respectively. Concentrations of brimonidine were measured using validated LC-MS/MS method. A naïve pool pharmacokinetic model was developed from the data obtained from the monkeys.
Results :
Brimonidine distributed into the tissue in the following order: R ≥ V > AH >plasma in both rabbits and monkeys, indicating targeted drug delivery to the retina. The duration of drug release was 30-61 and 60-92 days in rabbits and monkeys, respectively. The PK parameters are summarized in Table 1. Simulations for human vitreous and macula were conducted by fixing all the PK parameters to be the same as those in monkeys and scaling the vitreous volume to 4 mL. Based on the model prediction for brimonidine concentrations in human macula, Brimo DDS is anticipated to deliver drug above the efficacious levels (> 90 ng/g) for approximately 3 months in humans.
Conclusions :
Following intravitreal administration of Brimo DDS to rabbits and monkeys, targeted delivery of brimonidine to the retina was observed. Model predictions based on non-clinical data were used to inform the dosing frequency in the human clinical trial.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.