Netarsudil

Netarsudil, a Rho kinase inhibitor, is believed to reduce intraocular pressure (IOP) by increasing outflow of aqueous humor. Studies in animal and man suggest that the main mechanism of action is increased trabecular outflow. These studies also suggest that netarsudil lowers IOP by reducing episcleral venous pressure.

Absorption

The systemic exposures of netarsudil and its active metabolite, AR-13503, were evaluated in 18 healthy subjects after topical ocular administration of netarsudil once daily (one drop bilaterally in the morning) for 8 days. There were no quantifiable plasma concentrations of netarsudil (lower limit of quantitation (LLOQ) 0.100 ng/ml) post dose on day 1 and day 8. Only one plasma concentration at 0.11 ng/ml for the active metabolite was observed for one subject on day 8 at 8 hours post-dose.

Biotransformation

After topical ocular dosing, netarsudil is metabolised by esterases in the eye to an active metabolite, AR-13503.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to development. Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Intravenous administration of netarsudil mesylate to pregnant rats and rabbits during organogenesis did not produce adverse embryofetal effects at clinically relevant systemic exposures. In pregnant rats, 0.3 mg/kg/day (1000 times the recommended ophthalmic dose) and higher showed increased postimplantation loss and reduced foetal viability. In pregnant rabbits, 3 mg/kg/day (10000 times the recommended ophthalmic dose) and higher showed an increase in post-implantation loss and a decrease in foetal weight.

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of netarsudil.

Netarsudil was not mutagenic in a bacterial mutation assay, in a mouse lymphoma assay, or in a rat micronucleus test.

Netarsudil and its active metabolite AR-13503 was found to have a possible phototoxic potential in a modified 3T3 NRU-PT in vitro assay, where the wavelength was extended to include UVB light.