title: 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.
authors.affiliation: Clinical Pharmacology, Global Development, Astellas Pharma Inc., Tokyo, Japan, takeshi.kadokura@astellas.com.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kadokura
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zhang
authors.forename: Walter
authors.initials: W
authors.lastname: Krauwinkel
authors.forename: Stefanie
authors.initials: S
authors.lastname: Leeflang
authors.forename: James
authors.initials: J
authors.lastname: Keirns
authors.forename: Yuta
authors.initials: Y
authors.lastname: Taniuchi
authors.forename: Ikumi
authors.initials: I
authors.lastname: Nakajo
authors.forename: Ronald
authors.initials: R
authors.lastname: Smulders
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D005960:Glucosides / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D007564:Japan; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000503:physiopathology; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; C089180:SLC5A2 protein, human; C572941:ipragliflozin