Pharmacokinetics and safety of nafamostat and its metabolites following single- and multiple-dose oral administration of nafamostat mesylate in healthy male participants.

Abstract

Nafamostat mesylate, a serine protease inhibitor, is a potential antiviral agent that inhibits the intracellular entry of severe acute respiratory syndrome coronavirus-2. An oral formulation is under development to improve patient compliance over the existing intravenous formulation. This study evaluated the pharmacokinetics (PKs) and safety of oral nafamostat mesylate following single and multiple doses in healthy male participants. An open-label, single-dose and multiple ascending dose (MAD) study was conducted. In the single-dose study, 8 participants were administered 200 mg of nafamostat mesylate. In the MAD study, 8 participants in each dose group received nafamostat mesylate 100, 200, or 400 mg every 6 hours (QID) for 7 days. PKs were assessed for nafamostat in the single-dose study, and for nafamostat, 6-amidino-2-naphthol (AN) and 4-guanidinobenzoic acid (GBA) in the MAD study. The safety and tolerability were evaluated throughout the study. The median time to maximum concentration at steady state was 0.50-0.88 hours for nafamostat, 1.75-2.00 hours for AN, and 2.50-3.50 hours for GBA. Terminal elimination half-life ranged 0.61-3.84, 21.24-31.44, and 8.28-14.70 hours respectively. The accumulation ratio of nafamostat was 23.86 at 400 mg QID, with no accumulation at 100 and 200 mg QID. The mean accumulation ratios were 7.43-13.73 for AN and 1.84-2.11 for GBA. Nafamostat exposure showed a more than dose-proportional increase, whereas metabolites exposures were dose-proportional. No serious adverse events were reported. Multiple doses of oral nafamostat mesylate were well-tolerated up to 400 mg QID in healthy male participants.

Trial registration: Clinical Research Information Service Identifier: KCT0005647.