|Pharmacokinetic and Pharmacodynamic Properties of Single- and Multiple-Dose of Dapagliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects|
|Yang, Li1; Li, Haiyan1; Li, Hongmei2; Bui, Anh3; Chang, Ming3; Liu, Xiaoni4; Kasichayanula, Sreeneeranj3; Griffen, Steven C.3; LaCreta, Frank P.3; Boulton, David W.3|
|关键词||Chinese Dapagliflozin Pharmacodynamics Pharmacokinetics Sglt2 Type 2 Diabetes Mellitus|
|WOS标题词||Science & Technology|
|类目[WOS]||Pharmacology & Pharmacy|
|研究领域[WOS]||Pharmacology & Pharmacy|
|关键词[WOS]||INADEQUATE GLYCEMIC CONTROL ; TYPE-2 DIABETES-MELLITUS ; PLACEBO-CONTROLLED TRIAL ; RENAL GLUCOSURIA TYPE-0 ; DOUBLE-BLIND ; METFORMIN ; PATIENT ; INSULIN|
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/m(2) in the dapagliflozin 5- and 10-mg studies, respectively. In both doses, dapagliflozin was rapidly absorbed (T-max, <= 1.5 h), accumulation (defined as the geometric mean ratio of AUC(tau) at day 10 to AUC(tau) 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 (<= 2 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 <= 1.9% 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. (C) 2013 Elsevier HS Journals, Inc. All rights reserved.
|作者单位||1.Peking Univ, Hosp 3, Beijing 100871, Peoples R China|
2.Bristol Myers Squibb Co, Shanghai, Peoples R China
3.Bristol Myers Squibb Co, Discovery Med & Clin Pharmacol, Princeton, NJ USA
4.Bristol Myers Squibb Co, Global Biometr Sci, Princeton, NJ USA
|Yang, Li,Li, Haiyan,Li, Hongmei,et al. Pharmacokinetic and Pharmacodynamic Properties of Single- and Multiple-Dose of Dapagliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects[J]. CLINICAL THERAPEUTICS,2013,35(8):1211-1222.|
|APA||Yang, Li.,Li, Haiyan.,Li, Hongmei.,Bui, Anh.,Chang, Ming.,...&Boulton, David W..(2013).Pharmacokinetic and Pharmacodynamic Properties of Single- and Multiple-Dose of Dapagliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects.CLINICAL THERAPEUTICS,35(8),1211-1222.|
|MLA||Yang, Li,et al."Pharmacokinetic and Pharmacodynamic Properties of Single- and Multiple-Dose of Dapagliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects".CLINICAL THERAPEUTICS 35.8(2013):1211-1222.|