The effects of netarsudil ophthalmic solution on aqueous humor dynamics in a randomized study in humans

Purpose: Netarsudil, an inhibitor of Rho kinase and a norepinephrine transporter, has been shown to lower elevated intraocular pressure (IOP) in controlled studies of patients with open-angle glaucoma and ocular hypertension, and in healthy volunteers. The mechanism of this ocular hypotensive effect in humans is unknown. Methods: The objective of this study was to evaluate the effect of netarsudil 0.02% on aqueous humor dynamics (AHD) parameters. In this double-masked, vehicle-controlled, paired-eye comparison study, 11 healthy volunteers received topical netarsudil ophthalmic solution 0.02% or its vehicle once daily for 7 days (morning dosing). The primary endpoints were the change in AHD parameters, compared between active and vehicle-treated eyes. Results: In netarsudil-treated eyes, diurnal outflow facility increased from 0.27 ± 0.10 μL/min/mmHg to 0.33 ± 0.11 μL/min/mmHg (+22%; P = 0.02) after 7 days of treatment. In placebo-treated eyes, diurnal outflow facility did not significantly change (P = 0.94). The difference between netarsudil and placebo eyes in diurnal change of outflow facility was 0.08 μL/min/mmHg (P < 0.001). Diurnal episcleral venous pressure (EVP) in netarsudil-treated eyes decreased from 7.9 ± 1.2 mmHg to 7.2 ± 1.8 (-10%; P = 0.01). Diurnal EVP was not significantly different between netarsudil- A nd placebo-treated eyes. There was a trend toward decreasing aqueous humor flow rate (-15%; P = 0.08). No treatment changes were seen in uveoscleral outflow rate. Conclusions: Once-daily dosing of netarsudil ophthalmic solution 0.02% lowered IOP through increasing trabecular outflow facility and reducing EVP. This suggests a combination of mechanisms that affect both the proximal and distal outflow pathways.