Abstract
Purpose :
Brimonidine DDS (Brimo DDS), a sustained-release, biodegradable polymer implant, containing brimonidine, is being developed for treatment of geographic atrophy (GA), secondary to age-related macular degeneration. We evaluated the ocular pharmacokinetics (PK) and implant bioerosion of Brimo DDS, tartrate salt (Gen 1) and free base (Gen 2) in rabbits and monkeys and systemic PK in clinical studies.
Methods :
Rabbits (4-6 eyes/timepoint) received intravitreal injection of either 132 µg or 264 µg Gen 1 or 400 µg Gen 2. Cynomolgus monkeys (2-3 eyes/timepoint) received either 132 µg Gen 1 or 400 µg Gen 2. Plasma, retina and vitreous concentrations of brimonidine were measured (LC-MS/MS). Polymer bioerosion in monkeys was evaluated up to 9 months for Gen 2 and up to 27 months for Gen 1. Implant remnants were removed at the end of study and weighed to compare pre-implantation and post-removal weights. Plasma concentrations were measured (LC-MS/MS) in patients dosed with Gen 1 (N=32-33) and Gen 2 (N=51).
Results :
Based on implant in vitro release profiles, targeted duration of drug release in vivo was 180 days for Gen 1 and 90 days for Gen 2. Duration of brimonidine exposure in both rabbit and monkey vitreous (Figure 1) was consistent with implant release profiles. Gen 1 brimonidine concentrations were measurable in the vitreous for 180 days in both species. Gen 2 concentrations were measurable for 90 days in rabbits and 160 days in monkeys (concentrations in monkeys were minimal post day 90). Exposure (AUC) in rabbit retina was substantially greater with Gen 2 than Gen 1. Concentrations in plasma were below limit of quantitation (〈0.5 ng/mL) in both species. Rapid bioerosion with Gen 2 implants was evident in monkeys, with only 3% of original implant weight remaining at 6 months versus 5% remaining at 27 months with Gen 1. A dose-exposure response was observed in human plasma as the exposure (AUC) was greater with Gen 2 than Gen 1 (Table 1).
Conclusions :
Formulation change from Gen 1 to Gen 2 led to faster brimonidine release, more rapid bioerosion and increased drug load, thereby providing higher ocular tissue exposures in animals. Increased systemic exposure in humans with Gen 2 is potentially indicative of increased ocular tissue exposure.
This is a 2020 ARVO Annual Meeting abstract.