Background: Ipragliflozin (ASP1941), a potent selective sodium glucose co-transporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. Ipragliflozin is primarily eliminated via conjugation by the liver as five pharmacologically inactive metabolites (M1, M2, M3, M4 and M6). This study evaluated the effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin and its metabolites.
Methods: In an open-label, single-dose, parallel-group study, 16 subjects (eight with moderate hepatic impairment [Child-Pugh score 7-9] and eight healthy, matched controls) received a single oral dose of 100-mg ipragliflozin. Plasma concentrations of ipragliflozin and its metabolites were determined. Adverse events (AEs) and other clinical laboratory parameters were monitored.
Results: All subjects completed the study. Least-squares geometric mean ratios (GMRs) (90 % confidence interval [CI]) for maximum plasma concentration (C max) and area under the plasma concentration-time curve from time zero to infinity (AUC∞) of ipragliflozin were 127 % (93-173 %) and 125 % (94-166 %), respectively, in moderate hepatic impairment versus controls. No changes in elimination half-life and protein binding of ipragliflozin were observed in moderate hepatic impairment subjects. Least-squares GMRs for C max and AUC∞ of M2, the major metabolite, were respectively 95 % (68-133 %) and 100 % (77-130 %) in moderate hepatic impairment versus controls. No deaths, other serious AEs or AEs leading to discontinuation occurred.
Conclusions: Moderate hepatic impairment had no clinically relevant effects on the single-dose pharmacokinetics of ipragliflozin and its major metabolite, M2. A single oral dose of ipragliflozin, 100 mg, was well tolerated in both healthy subjects and those with moderate hepatic impairment.