Clinical Pharmacokinetics and Pharmacodynamics of the Novel SGLT2 Inhibitor Ipragliflozin

Abstract

Ipragliflozin (Suglat(®)) is a potent and selective inhibitor of sodium-glucose cotransporter-2 that was recently launched in Japan. Its mechanism of action involves the suppression of glucose re-absorption in the kidney proximal tubules, causing excretion of glucose in the urine. The aim of this review is to provide a comprehensive overview of currently available pharmacokinetic and pharmacodynamic data on ipragliflozin, including studies in healthy subjects, patients with type 2 diabetes mellitus and special populations. In single- and multiple-dose studies, the maximum plasma concentration and area under the plasma concentration-time curve (AUC) for ipragliflozin increased in a dose-dependent manner. Although urinary excretion of ipragliflozin is low (approximately 1 %), tubular concentration of free ipragliflozin is adequate to provide pharmacological activities. No clinically relevant effects of age, gender or food on the exposure of ipragliflozin were observed. The AUC for ipragliflozin was 20-30 % greater in patients with moderate renal or hepatic impairment than in patients with normal renal or hepatic function. In drug-drug interaction studies, the pharmacokinetics of ipragliflozin and other oral antidiabetic drugs (metformin, sitagliptin, pioglitazone, glimepiride, miglitol and mitiglinide) were not significantly affected by their co-administration. Urinary glucose excretion (UGE) also increased in a dose-dependent manner, approaching a maximum effect at 50-100 mg dosages in Japanese healthy volunteers and patients with type 2 diabetes. The change in UGE from baseline (ΔUGE) tended to be lower in older subjects and female subjects, compared with younger subjects and male subjects, respectively. ΔUGE tended to decrease with decreasing renal function, especially in patients with type 2 diabetes with moderate or severe renal impairment.

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

“…The clinical pharmacokinetics and pharmacodynamics of the novel SGLT2i ipragliflozin, which has gained approval for clinical use in T2D in Japan, have been reviewed [68] . To investigate the effect of ipragliflozin on the pharmacokinetics of sitagliptin and vice versa, ipragliflozin 150 mg and sitagliptin 100 mg were administered alone or in combination in two cohorts of 32 healthy subjects [69] .…”

Comparison of tofogliflozin 20 mg and ipragliflozin 50 mg used together with insulin glargine 300 U/mL using continuous glucose monitoring (CGM): A randomized crossover study

“…Therefore, further decreases in nocturnal glucose levels are not thought to be caused due to intake of tofogliflozin. In contrast, ipragliflozin is thought to pose a risk of further decrease in nocturnal glucose levels, in combination with insulin because ipragliflozin has a long half-life, and therefore acts firmly during the nighttime [22]. We think that occurrence of nocturnal and overall hypoglycemia was significantly lower in patients on tofogliflozin, than in those on ipragliflozin because of the above-mentioned difference between tofogliflozin and ipragliflozin.…”

“…Therefore, this supports the hypothesis that the effect of tofogliflozin taken in the morning almost disappears during the nighttime. In contrast, it has been reported that Tmax of ipragliflozin is 1.4 hours and its half-life is 15 hours [22]. Therefore, ipragliflozin affects the individual for a constant duration (steady state).…”

“…Table 2 thought to occur because the effect of tofogliflozin is suggested to be stronger during the daytime (and weaker during the nighttime) than that of ipragliflozin even though there are no differences between the overall effects of tofogliflozin or ipragliflozin [10,11]. The reason of the following is estimated that a half-life of tofogliflozin is shorter than that of ipragliflozin [12,22]. In contrast, the nocturnal effect of ipragliflozin became less because SGLT2i decreases glucose levels in a glucose level-dependent manner.…”

“…In this study, MAGE, ADRR, and SD (24 hours) were significantly lower in patients on tofogliflozin, than in those on ipragliflozin. The effect of tofogliflozin which has a short half-life is suggested to be stronger during the daytime and disappears quickly during nighttime, as compared to that of ipragliflozin, even though there are no differences between the overall effects of tofogliflozin and ipragliflozin [10][11][12]22]. Therefore, daytime glucose levels were lower, and occurrence of nocturnal hypoglycemia was lower in patients on tofogliflozin, than in those on ipragliflozin.…”