Dapagliflozin, a Novel SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects

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 eva...

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Published in:Clinical pharmacology and therapeutics 2009-05, Vol.85 (5), p.520-526
Main Authors: Komoroski, B, Vachharajani, N, Boulton, D, Kornhauser, D, Geraldes, M, Li, L, Pfister, M
Format: Article
Language:English
Subjects:
Adult
Benzhydryl Compounds
Biological and medical sciences
Blood Glucose - drug effects
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - physiopathology
Dose-Response Relationship, Drug
Double-Blind Method
Glucosides - administration & dosage
Glucosides - adverse effects
Glucosides - pharmacokinetics
Glycosuria - chemically induced
Half-Life
Humans
Hypoglycemic Agents - administration & dosage
Hypoglycemic Agents - adverse effects
Hypoglycemic Agents - pharmacokinetics
Male
Medical sciences
Pharmacology. Drug treatments
Sodium-Glucose Transporter 2
Sodium-Glucose Transporter 2 Inhibitors
Time Factors
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Summary: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 ~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 ~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. Clinical Pharmacology & Therapeutics (2009); 85, 5, 520–526 doi:10.1038/clpt.2008.251
ISSN:0009-9236
1532-6535
DOI:10.1038/clpt.2008.251