Clinical Pharmacokinetics and Pharmacodynamics of Dapagliflozin, a Selective Inhibitor of Sodium-Glucose Co-transporter Type 2
- 3.2k Downloads
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.
KeywordsValsartan Sitagliptin Bumetanide Mefenamic Acid Biopharmaceutics Classification System
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.
- 1.International Diabetes Foundation. The global burden. International Diabetes Foundation Web site. http://www.diabetesatlas.org/book/export/html/36. Accessed 4 Mar 2013.
- 2.World Diabetes Foundation. Diabetes facts. World Diabetes Foundation Web site. http://www.worlddiabetesfoundation.org/composite-35.html. Accessed 4 Mar 2013.
- 3.World Health Organisation. Global strategy on diet, physical activity and health. World Health Organisation Web site. http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/. Accessed 4 Mar 2013.
- 6.Hermans MP, Brotons C, Elisaf M, et al. Optimal type 2 diabetes mellitus management: the randomised controlled OPTIMISE benchmarking study: baseline results from six European countries. Eur J Prev Cardiol. 2012. doi: 10.1177/2047487312449414.
- 15.Ptaszynska A, Johnsson K, Apanovitch A, et al. Safety of dapagliflozin in clinical trials for T2DM. Diabetes. 2012;61(suppl 1):A258–9.Google Scholar
- 18.Zinker B, Ma X, Liu H, et al. Chronic dapagliflozin treatment reduces elevated hepatic glucose production and enhances pancreatic insulin content in male ZDF rats. (Abstract 1031-P). Diabetes. 2011;60(suppl 1):A283.Google Scholar
- 19.Forxiga: Summary of Product Characteristics. AstraZeneca and Bristol-Myers Squibb. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002322/WC500136026.pdf. Accessed 8 Apr 2013.
- 23.Kasichayanula S, Yao M, Vachharajani M, et al. Disposition and Mass Balance of [14C]-dapagliflozin after single oral dose in healthy male volunteers. AAPS J. 2008;10(S2).Google Scholar
- 30.DeFronzo RA, Hompesch M, Kasichayanula S, et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care. 2013 [Epub ahead of print].Google Scholar
- 34.Yang L, Li H, Li H, et al. Pharmacokinetic and pharmacodynamic properties of single- and multiple-dose of dapagliflozin, a selective inhibitor of SGLT2, in healthy Chinese subjects. Clin Ther. 2013;35(8):1211–22.e2.Google Scholar
- 36.Imamura A, Kusunoki M, Ueda S, et al. Impact of voglibose on the pharmacokinetics of dapagliflozin in Japanese patients with type 2 diabetes. Diabetes Ther. 2013;4(1):41–9.Google Scholar
- 38.Wilcox CS, Liu X, Kasichayanula S, et al. Evaluation of interactions of dapagliflozin and bumetanide. Presented at: American Society of Nephrology, Denver (2010).Google Scholar