Pharmacokinetic and Pharmacodynamic Properties of Single- and Multiple-Dose of Dapagliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects

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• 作者：Li Yang ; Haiyan Li ; Hongmei Li ; Anh Bui ; Ming Chang ; Xiaoni Liu ; Sreeneeranj Kasichayanula ; Steven C. Griffen ; Frank P. LaCreta ; David W. Boulton
• 关键词：Chinese ; dapagliflozin ; pharmacodynamics ; pharmacokinetics ; SGLT2 ; type 2 diabetes mellitus
• 刊名：Clinical Therapeutics
• 出版年：2013
• 出版时间：August, 2013
• 年：2013
• 卷：35
• 期：8
• 页码：1211-1222.e2
• 全文大小：249 K

文摘

Background

Dapagliflozin, a selective, orally active, renal sodium glucose cotransporter 2 (SGLT2) 2 inhibitor, is under investigation as a treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin reduces hyperglycemia by inhibiting renal glucose reabsorption and dose-dependently increasing urinary glucose excretion, independent of insulin secretion or action.

Objectives

These studies assessed the single- and multiple-dose pharmacokinetic and pharmaco dynamic properties of dapagliflozin and its major inactive metabolite, dapagliflozin 3-O-glucuronide (D3OG), in healthy subjects residing in China.

Methods

In 2 identically designed, open-label, single- and multiple-dose studies (n = 14 for both studies), healthy Chinese subjects were administered oral dapagliflozin 5 or 10 mg. In both studies, subjects received a single dose on day 1 (single-dose administration period) followed by 6 once-daily doses on days 5 to 10 (multiple-dose administration period). Pharmacokinetic parameters (plasma and urinary dapagliflozin and D3OG), pharmacodynamic response (urinary glucose excretion), and tolerability were assessed.

Results

Fourteen subjects completed the dapagliflozin 5-mg study, and 13 completed the dapagliflozin 10-mg study. Baseline characteristics were balanced across the two studies: 9 versus 10 men; mean age, 27.1 versus 28.9 years; mean weight, 62.8 versus 62.2 kg; and mean body mass index, 23.0 versus 22.2 kg/m² in the dapagliflozin 5- and 10-mg studies, respectively. In both doses, dapagliflozin was rapidly absorbed (T_max, ¡Ü1.5 h), accumulation (defined as the geometric mean ratio of AUC_¦Ó at day 10 to AUC_¦Ó at day 1) after multiple dosing was minimal (<1.13 fold), and elimination half-life was 10 to 12 h. D3OG showed a slightly longer median T_max (¡Ü2 h) but a similar plasma concentration-time profile and half-life compared with dapagliflozin. The majority of D3OG (up to 69.7 % of the dapagliflozin dose) was excreted in urine, while ¡Ü1.9 % of dapagliflozin was excreted unchanged in urine. Over a 24-hour period and at steady state (day 10), urinary glucose excretion values were 28.1 and 41.1 g with dapagliflozin 5 and 10 mg, respectively. Dapagliflozin was generally well tolerated; one dapagliflozin 10 mg-treated subject discontinued the study because of a serious adverse event (bronchitis) considered by the investigator as unrelated to dapagliflozin dosing.

Conclusions

Pharmacokinetic and pharmacodynamic characteristics following single- and multiple-dose dapagliflozin 5 and 10 mg oral administration in healthy Chinese subjects were as predicted from previous studies and were similar to findings observed in non-Chinese healthy subjects. Dapagliflozin dosing was well tolerated. The clinically recommended dapagliflozin dose of 10 mg once daily is expected to be appropriate in patients of Chinese ethnicity; results from an efficacy and tolerability study in Chinese patients with T2DM are awaited.