Pharmacodynamic response of optic nerve head (ONH) tissue blood flow measured by laser speckle flowgraphy (LSFG) after administration of PER-001, an endothelin receptor antagonist

Abstract

Purpose : Reduction of ocular blood flow in glaucoma is thought to be related to upregulation of the endothelin system. Our purpose here was to determine the time course and dose dependency of ONH tissue blood flow in response to a single administration of PER-001.

Methods : LSFG (Softcare Co., Ltd.) was used to measure ONH tissue blood flow (as previously described in detail, PMID: 23737471) in 6 anesthetized adult rhesus monkeys (Macaca mulatta, 4F/2M ages 7-12 y) with unilateral experimental glaucoma (EG). Three LSFG scans were obtained for each eye and averaged at each time point, starting 30 min prior to bilateral intravitreal administration of 50 µL of PER-001 or vehicle, and thereafter every 15-30 min for 6 hr. The dose of PER-001 was varied in random order between 0.001, 0.01, 0.1 mg or vehicle for each subject. The effects of dose, time after administration and eye (EG vs fellow control, FC) were assessed using repeated measures ANOVA, mixed-effects models and generalized estimating equations to include effects of an array of vital signs.

Results : At the beginning of the series of 4 weekly PER-001 assays, ONH neuroretinal minimum rim width in EG and FC eyes, respectively was 155 ± 74 vs 291 ± 39 µm (p=0.005); peripapillary retinal nerve fiber layer thickness was 77 ± 21 vs 100 ± 8.5 µm (p=0.04); and mean blur rate (MBR) from LSFG was 12.3 ± 3.0 vs 14.2 ± 4.9 (p = 0.18); thus, representing a moderate stage of EG damage. Following administration of PER-001 (Figs.1,2), LSFG MBR increased significantly in EG eyes with time after injection (p<0.0001), indicating increased flow; there was a significant time-dose interaction (p<0.0001) and effect of dose (p=0.0006). Whereas, in FC eyes, only the effect of time after injection was significant (p<0.0001). The effect of PER-001 on ONH blood flow was relatively greater in EG eyes such that blood flow increased to a level comparable to FC eyes after ~4 hr, for the mid and high dose. This pattern held after controlling for end-tidal CO₂, the only vital sign significantly associated with MBR.

Conclusions : ONH tissue blood flow increased in a dose-dependent manner after administration of PER-001. The effect was more prominent in EG compared to FC eyes, consistent with the hypothesis that upregulation of the endothelin system contributes to reduction of blood flow in glaucoma.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.