title: Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects.
abstract: Dapagliflozin selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter-2 (SGLT2). It was developed as an insulin-independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug were evaluated in single-ascending-dose (SAD; 2.5-500 mg) and multiple-ascending-dose (MAD; 2.5-100 mg daily for 14 days) studies in healthy subjects. Dapagliflozin exhibited dose-proportional plasma concentrations with a half-life of approximately 17 h. The amount of glucosuria was also dose-dependent. Cumulative amounts of glucose excreted on day 1, relating to doses from 2.5-100 mg (MAD), ranged from 18 to 62 g; day 14 values were comparable to day 1 values, with no apparent changes in glycemic parameters. Doses of approximately 20-50 mg provided close-to-maximal SGLT2 inhibition for at least 24 h. Dapagliflozin demonstrates pharmacokinetic (PK) characteristics and dose-dependent glucosuria that are sustained over 24 h, which indicates that it is suitable for administration in once-daily doses and suggests that further investigation of its efficacy in T2DM patients is warranted.
authors.affiliation: Discovery Medicine and Clinical Pharmacology, Research and Development, Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: B
authors.initials: B
authors.lastname: Komoroski
authors.forename: N
authors.initials: N
authors.lastname: Vachharajani
authors.forename: D
authors.initials: D
authors.lastname: Boulton
authors.forename: D
authors.initials: D
authors.lastname: Kornhauser
authors.forename: M
authors.initials: M
authors.lastname: Geraldes
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Pfister
mesh_terms: D000328:Adult; D001559:Benzhydryl Compounds; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005960:Glucosides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006029:Glycosuria / Q000139:chemically induced*; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013997:Time Factors
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C529054:dapagliflozin