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Clinical Pharmacokinetics

, Volume 53, Issue 1, pp 17–27 | Cite as

Clinical Pharmacokinetics and Pharmacodynamics of Dapagliflozin, a Selective Inhibitor of Sodium-Glucose Co-transporter Type 2

  • Sreeneeranj KasichayanulaEmail author
  • Xiaoni Liu
  • Frank LaCreta
  • Steven C. Griffen
  • David W. Boulton
Review Article

Abstract

Sodium-glucose co-transporter 2 (SGLT2) is predominantly expressed in the S1 segment of the proximal tubule of the kidney and is the major transporter responsible for mediating renal glucose reabsorption. Dapagliflozin is an orally active, highly selective SGLT2 inhibitor that improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by reducing renal glucose reabsorption leading to urinary glucose excretion (glucuresis). Orally administered dapagliflozin is rapidly absorbed generally achieving peak plasma concentrations within 2 h. Dose-proportional systemic exposure to dapagliflozin has been observed over a wide dose range (0.1–500 mg) with an oral bioavailability of 78 %. Dapagliflozin has extensive extravascular distribution (mean volume of distribution of 118 L). Dapagliflozin metabolism occurs predominantly in the liver and kidneys by uridine diphosphate-glucuronosyltransferase-1A9 to the major metabolite dapagliflozin 3-O-glucuronide (this metabolite is not an SGLT2 inhibitor at clinically relevant exposures). Dapagliflozin is not appreciably cleared by renal excretion (<2 % of dose is recovered in urine as parent). Dapagliflozin 3-O-glucuronide elimination occurs mainly via renal excretion, with 61 % of a dapagliflozin dose being recovered as this metabolite in urine. The half-life for orally administered dapagliflozin 10 mg was 12.9 h. Maximal increases in urinary glucose excretion were seen at doses ≥20 mg/day in patients with T2DM. No clinically relevant differences were observed in dapagliflozin exposure with respect to age, race, sex, body weight, food, or presence of T2DM. Pharmacodynamic changes are dependent on plasma glucose and renal function, and decreases in urinary glucose excretion were observed due to the lower filtered load (plasma glucose × glomerular filtration rate) in healthy volunteers compared to subjects with T2DM. After multiple doses of dapagliflozin, urinary glucose excretion was associated with dose-related decreases in plasma glucose parameters in subjects with T2DM. Patients with severe renal or hepatic impairment show higher systemic exposure to dapagliflozin. No clinically relevant drug interactions were observed that would necessitate dose adjustment of dapagliflozin when administered with other antidiabetic or cardiovascular medications, as well as drugs that could potentially influence dapagliflozin metabolism.

Keywords

Valsartan Sitagliptin Bumetanide Mefenamic Acid Biopharmaceutics Classification System 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

Medical writing assistance was provided by Ray Ashton and Karen Pemberton, PhD of PPSI (a PAREXEL company) and was funded by AstraZeneca and Bristol-Myers Squibb. All authors are employees of Bristol-Myers Squibb.

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Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Sreeneeranj Kasichayanula
    • 1
    Email author
  • Xiaoni Liu
    • 1
  • Frank LaCreta
    • 1
  • Steven C. Griffen
    • 1
  • David W. Boulton
    • 1
  1. 1.Bristol-Myers Squibb CoPrincetonUSA

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