Journal
DIABETES OBESITY & METABOLISM
Volume 13, Issue 4, Pages 357-365Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1463-1326.2011.01359.x
Keywords
antidiabetic drug; clinical trial; pharmacodynamics; pharmacokinetics; SGLT2 inhibitor; type 2 diabetes; Japanese
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Funding
- Bristol-Myers Squibb Company
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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.
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