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Dapagliflozin, a Novel SGLT2 Inhibitor, Induces Dose‐Dependent Glucosuria in Healthy Subjects
Author(s) -
Komoroski B,
Vachharajani N,
Boulton D,
Kornhauser D,
Geraldes M,
Li L,
Pfister M
Publication year - 2009
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2008.251
Subject(s) - dapagliflozin , pharmacokinetics , tolerability , pharmacology , pharmacodynamics , medicine , renal glucose reabsorption , reabsorption , glycemic , clinical pharmacology , diabetes mellitus , type 2 diabetes , endocrinology , chemistry , kidney , adverse effect
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