Ipragliflozin (ASP1941), a selective sodium-dependent glucose cotransporter 2 inhibitor, safely stimulates urinary glucose excretion without inducing hypoglycemia in healthy Japanese subjects

Abstract

Background This phase 1, randomized, placebo-controlled, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of ipragliflozin (ASP1941) in healthy Japanese subjects. Methods Subjects received a single oral dose (1-300 mg) of ipragliflozin or multiple once-daily oral doses (20-100 mg) for 7 days. The effect of food on pharmacokinetics and pharmacodynamics was explored by administering a single dose of 100 mg in the fasting and fed states. Adverse events were recorded throughout the study. Results Ipragliflozin was well tolerated. Adverse events were mild, none was hypoglycemia related, and no urinary or genital infections were reported. Ipragliflozin was rapidly absorbed, reaching maximum plasma concentration within 3 h. Maximum plasma concentration and area under the plasma concentration-time curve increased dose-proportionally. Plasma half-life was reached 10.0-13.3 h after the first dose of ipragliflozin C3 mg, and no dose-dependent relationship was observed. Food had no significant impact on the pharmacokinetics and pharmacodynamics of ipragliflozin. Plasma glucose levels were not significantly affected by ipragliflozin administration. Urinary glucose excretion increased dose-dependently. A maximum of approximately 70 and 50 g of glucose excreted over 24 h was reached after single 300 mg dosing and after multiple 50 or 100 mg dosing, respectively. Conclusions Ipragliflozin was well tolerated and stimulated dose-dependent increases in urinary glucose excretion in healthy Japanese subjects.

No pharmacokinetic interaction between ipragliflozin and sitagliptin, pioglitazone, or glimepiride in healthy subjects

“…Ipragliflozin is a potent, selective inhibitor of SGLT2 that increases UGE in Caucasian and Japanese healthy subjects as well as in patients with T2DM . The pharmacokinetics of ipragliflozin are consistent with the results previously reported in healthy subjects .…”

“…Ipragliflozin (ASP1941) is a potent, selective inhibitor of SGLT2, in clinical development (phase 3) for the treatment of patients with T2DM. Clinical studies have shown that ipragliflozin increases urinary glucose excretion (UGE) in healthy Caucasian and Japanese healthy subjects (figure 1) [12,13]. The increase in UGE caused by ipragliflozin leads to a decrease in hyperglycaemia in T2DM patients [14].…”

A quantitative LC–MS/MS method for determining ipragliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, and its application to a pharmacokinetic study in rats

“…t 1/2 , CL/F, and, Vd/F were 7.6 ± 2.0 h, 0.38 ± 0.13 L/h/kg, and, 4.4 ± 2.6 L/kg, respectively, and the plasma concentration of ipragliflozin 24 h after the oral administration of ipragliflozin to rats (22.9 ± 5.2 ng/mL) was determined. These pharmacokinetic parameters in rats were relatively close to those in humans [1,4,12]. These results suggest that the assay method is valuable for evaluating the pharmacokinetics of ipragliflozin in rats.…”

Safety, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Luseogliflozin Dosing in Healthy Japanese Males: A Randomized, Single-Blind, Placebo-Controlled Trial

“…The incremental change in UGE was smaller at higher doses of luseogliflozin than at lower doses. The maximum amount of daily UGE after luseogliflozin administration was comparable to that after administration of other SGLT2 inhibitors (dapagliflozin, canagliflozin, empagliflozin, and ipragliflozin) in healthy subjects, which was approximately 70 g/day after single dose and approximately 50–55 g/day after multiple dose [26, 35–38]. Further, the doses of luseogliflozin used in these studies (up to 25 mg for SAD study and 10 mg for MAD study) were lower than those used in previous tests of SGLT2 inhibitors (50–800 mg at the maximum dose in each study).…”