Abstract
Purpose :
Due to the shortage in supply of non-human primates (NHPs), the use of NHPs in non-clinical research for small molecules is now limited. Accordingly, obtaining pharmacokinetics (PK) data from alternative higher-order species (e.g., minipigs and dogs) is a valuable resource for informing appropriate species selection for future studies. The purpose was to evaluate ocular PK of dexamethasone (DEX) in minipigs and dogs for up to 3 months after a single intravitreal (IVT) DEX implant.
Methods :
Beagle dogs (n=2 eyes/terminal timepoint) and Göttingen minipigs (n=2 eyes/terminal timepoint) were administered an IVT DEX implant in both eyes. Nonterminal sampling included serial aqueous humor (AH) tap collection. Terminal sampling was conducted on days 21 and 90 post-dose, which included vitreous humor (VH), retina, choroid, AH, and iris-ciliary body. DEX was quantified using liquid chromatography tandem mass spectrometry with a lower limit of quantification (LLOQ) of 0.1 ng/mL for AH and 0.03 ng/g for ocular tissues. Historical PK data in rabbits and NHPs were used for cross-study comparison.
Results :
VH samples containing implant remnants at time of sacrifice were analyzed as a single sample to estimate drug release over time (Figure 1). At day 21, ~50% of drug was released in dogs, indicating fast release similar to rabbits. In minipigs, only ~10% of drug was released at day 21, indicating a much slower initial release compared to NHPs. DEX was fully released from implants by day 90 for both dog and minipig. Therefore, drug release rates could not be estimated since drug was only measurable at a single timepoint. A majority of drug was released (>90%) by day 30 and 90 in rabbits and NHPs, respectively. AH data supported the release findings from VH (Figure 2). AH data showed fast release in dogs, similar to rabbit. For minipigs, AH showed a slow initial release and shorter overall release duration compared to NHPs.
Conclusions :
This study was designed to guide selection of species for IVT DEX implant using only two animals per species by utilizing serial AH sampling and effective timepoint selection. VH and AH data suggest that release duration is much shorter in dogs compared to NHPs, whereas minipigs do not mimic NHPs in neither release onset nor duration. Therefore, neither species is deemed to be an appropriate replacement for NHPs in ocular PK studies for DEX IVT implants.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.