Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium-glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus

• Published in: Diabetes, obesity & metabolism Vol. 13; no. 4; pp. 357 - 365
• Main Authors: Kasichayanula, S, Chang, M, Hasegawa, M, Liu, X, Yamahira, N, LaCreta, F.P, Imai, Y, Boulton, D.W
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2011; Wiley Subscription Services, Inc
• Subjects: Administration, Oral; Adult; Adverse events; antidiabetic drug; Antidiabetics; Asian Continental Ancestry Group; Benzhydryl Compounds; clinical trial; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - physiopathology; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glucose; Glucose transporter; Glucosides - pharmacokinetics; Glucosides - pharmacology; Humans; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Japanese; Male; Middle Aged; Pharmacodynamics; Pharmacokinetics; Plasma; SGLT2 inhibitor; Sodium-Glucose Transporter 2 - pharmacokinetics; Sodium-Glucose Transporter 2 - pharmacology; Treatment Outcome; type 2 diabetes
• ISSN: 1462-8902; 1463-1326; 1463-1326
• DOI: 10.1111/j.1463-1326.2011.01359.x

Aims: Dapagliflozin, a selective, orally active inhibitor of the renal sodium-glucose co-transporter type 2 (SGLT2) is in development for the treatment of type 2 diabetes mellitus (T2DM). Here, the pharmacokinetics (PK) and pharmacodynamics (PD) of dapagliflozin were evaluated in healthy Japanese subjects and in Japanese subjects with T2DM. Methods: Two studies were conducted: a single-ascending dose (SAD) study (2.5-50 mg) in 32 healthy subjects and a multiple-ascending dose (MAD) study (2.5-20 mg QD for 14 days) in 36 subjects with T2DM. Safety and tolerability were assessed in both studies. Single and multiple dose PK of dapagliflozin and its inactive major metabolite, dapagliflozin 3-O-glucuronide, and PD (urinary glucose parameters) were characterized. Plasma glucose parameters were assessed over 14 days in the MAD study. Results: No serious adverse events or discontinuations due to adverse events occurred in either study. In healthy and T2DM subjects, dapagliflozin was rapidly absorbed with a time to maximum plasma concentration of 0.5-1.3 h. Systemic exposure of dapagliflozin and dapagliflozin 3-O-glucuronide, measured by maximum plasma concentration and area under the plasma concentration-time curve, increased proportional to dose. On a molar basis, systemic exposure to dapagliflozin 3-O-glucuronide was similar to parent dapagliflozin. There was a dose-related increase in the amount of glucose excreted in the urine (SAD and MAD), which was associated with dose-related decreases in plasma glucose parameters in subjects with T2DM (MAD). Conclusions: Dapagliflozin was well tolerated and showed predictable dose-proportional PK and PD parameters in both healthy and T2DM Japanese subjects.