Pharmacokinetic and pharmacodynamic study of ipragliflozin in Japanese patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled study☆
Introduction
Sodium–glucose transporter 2 (SGLT2) is a member of the SGLT family of solute transporters. It is highly expressed in proximal tubules in the kidney, where it plays a key role in glucose reabsorption [1]. Inhibition of SGLT2 was demonstrated to suppress renal glucose reabsorption and therefore enhance urinary glucose excretion (UGE) in vivo [2]. Consequently, inhibition of SGLT2 was proposed as an insulin-independent approach for treating type 2 diabetes mellitus (T2DM) [3]. Several SGLT2 inhibitors, including ipragliflozin, have since been developed, representing a new class of oral hypoglycemic agents.
Ipragliflozin is a potent and selective inhibitor of SGLT2 in vitro, and increases UGE in a dose-dependent manner in vivo [4]. Studies in healthy volunteers have confirmed that ipragliflozin also dose-dependently increases UGE in humans [5], [6]. Subsequent studies have shown that ipragliflozin, by enhancing UGE, decreases fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) in patients with T2DM [7], [8].
In a phase II study conducted in Japanese patients, treatment with 50 or 100 mg ipragliflozin for 12 weeks led to significant reductions in HbA1c, FPG, and body weight [5]. To date, however, the pharmacodynamic and pharmacokinetic properties of ipragliflozin in Japanese patients with T2DM have not been reported. Therefore, we conducted a 14-day, placebo-controlled, pharmacokinetic/pharmacodynamic study to determine the effects of two doses of ipragliflozin on daily plasma glucose profiles and urinary glucose excretion, specifically in Japanese patients with T2DM.
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Patients
Eligible patients were aged 20–74 years, had been diagnosed with T2DM for ≥12 weeks, were drug-naive or on monotherapy, had a body mass index (BMI) of 20–45 kg/m2, HbA1c (NGSP units) of 7.4–10.5%, FPG levels of ≥126 to <240 mg/dL, and fasting serum C-peptide level of >0.6 ng/mL. Patients previously using oral hypoglycemic drugs entered a mandatory washout period of 13 days before starting the present study. Patients were excluded from the study if they had advanced diabetes complications
Patient disposition and characteristics
Between November 2009 and March 2010, 30 patients were enrolled in this study. Two patients discontinued during the treatment period because of TEAEs (one each treated with 50 and 100 mg ipragliflozin), so no pharmacokinetic or pharmacodynamic data at the end of treatment could be obtained for these patients. Therefore, 28 patients were included in the PDAS and PKAS. All 30 patients were included in the SAF. Table 1 summarizes the characteristics of patients in each group, using the PDAS.
Discussion
Ipragliflozin is a potent and selective inhibitor of SGLT2 in vitro, and increases UGE in a dose-dependent manner in vivo [4]. Clinical studies have demonstrated that ipragliflozin increases UGE in healthy subjects without changing plasma glucose levels [5], [6]. In healthy Japanese subjects, up to 70 g of glucose was excreted over 24 h after a single 300 mg dose, while up to 50 g of glucose was excreted over 24 h after multiple doses of 50 or 100 mg [5]. The present study showed that 24-h UGE after
Disclosure
TK, NA, AU, KK, SY, and IN are employees of Astellas Pharma Inc. RS is an employee of Astellas Pharma Global Development. AK and SK have acted as consultants for Astellas Pharma Inc.
Conflicts of Interest
There is no conflict of interest.
Acknowledgements
Ipragliflozin is under development by Astellas Pharma Inc. and Kotobuki Pharmaceutical Co., Ltd. This study was sponsored by Astellas. Medical writing and editorial support was funded by Astellas and provided by Dr. Nicholas D. Smith and ELMCOM™.
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Results of this study were presented as a poster at the 71st Scientific Sessions of the American Diabetes Association, San Diego, CA, USA (June 24–28, 2011) and at the 55th Annual Meeting of the Japan Diabetes Society, Yokohama, Japan (May 17–19, 2012).