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

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.