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

• Published in: Clinical therapeutics Vol. 35; no. 8; pp. 1211 - 1222.e2
• Main Authors: Yang, Li, MS, Li, Haiyan, MD, Li, Hongmei, MD, Bui, Anh, BSN, Chang, Ming, MS, Liu, Xiaoni, PhD, Kasichayanula, Sreeneeranj, PhD, Griffen, Steven C., MD, LaCreta, Frank P., PhD, Boulton, David W., PhD
• Format: Journal Article
• Language: English
• Published: Bridgewater, NJ EM Inc USA 01.08.2013; Elsevier; Elsevier Limited
• Subjects: Administration, Oral; Adolescent; Adult; Benzhydryl Compounds; Biological and medical sciences; China; Chinese; dapagliflozin; Diabetes; Diabetes. Impaired glucose tolerance; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug dosages; Drugs, Investigational; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; FDA approval; Female; Glucose; Glucosides - administration & dosage; Glucosides - adverse effects; Glucosides - pharmacokinetics; Healthy Volunteers; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - pharmacokinetics; Insulin; Insulin resistance; Internal Medicine; Male; Medical Education; Medical sciences; Middle Aged; pharmacodynamics; pharmacokinetics; Pharmacology. Drug treatments; Rodents; SGLT2; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Studies; type 2 diabetes mellitus; Urine; Young Adult; Asia; China; pharmacokinetics; type 2 diabetes mellitus; Chinese; SGLT2; dapagliflozin; pharmacodynamics; Endocrinopathy; Type 2 diabetes; Human; Pharmacokinetic pharmacodynamic relationship; Pharmacodynamics; Healthy subject; Dapagliflozin; Single dose; Metabolic diseases; SGLT2 inhibitor; Biological activity; Multiple dose; Hypoglycemic agent; Pharmacokinetics
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2013.06.017

Abstract 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 (Tmax , ≤1.5 h), accumulation (defined as the geometric mean ratio of AUCτ at day 10 to AUCτ 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 Tmax (≤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.