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Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus.


ABSTRACT: INTRODUCTION:This study examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of empagliflozin, a potent and highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS:A total of 48 patients with T2DM were randomized to receive one of four doses of empagliflozin (2.5, 10, 25, or 100 mg qd) or placebo over 8 days. In every dose group, nine patients received active drug and three received placebo. The primary endpoint was safety and tolerability. Pharmacokinetic and pharmacodynamic parameters were measured as secondary endpoints. RESULTS:Empagliflozin was rapidly absorbed, reaching peak levels 1.5-3.0 h after dosing and showed a biphasic decline. The mean terminal elimination half-life ranged from 10 to 19 h. Increases in exposure (area under the plasma concentration-time curve [AUC] and maximum concentration of analyte in plasma [C max]) were approximately proportional with dose. Empagliflozin increased the rate and total amount of glucose excreted in urine compared to placebo. After administration of a single dose of empagliflozin, cumulative amounts of glucose excreted in urine over 24 h ranged from 46.3 to 89.8 g, compared with 5.84 g with placebo. Similar results were seen after multiple doses. Fasting plasma glucose levels decreased by 17.2-25.8% with empagliflozin and by 12.7% with placebo. The frequency of adverse events was 33.3-66.7% with empagliflozin and 41.7% with placebo. There were no changes in urine volume or micturition frequency under the controlled study conditions. CONCLUSION:Overall, pharmacokinetic assessments demonstrated a dose-proportional increase in drug exposure and support once-daily dosing. Elevated urinary glucose excretion was observed with all doses. Multiple once-daily oral doses of empagliflozin (2.5-100 mg) reduced plasma glucose and were well tolerated in patients with T2DM. EudraCT (2007-000654-32).

SUBMITTER: Heise T 

PROVIDER: S-EPMC3889329 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus.

Heise Tim T   Seman Leo L   Macha Sreeraj S   Jones Peter P   Marquart Alexandra A   Pinnetti Sabine S   Woerle Hans J HJ   Dugi Klaus K  

Diabetes therapy : research, treatment and education of diabetes and related disorders 20130710 2


<h4>Introduction</h4>This study examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of empagliflozin, a potent and highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM).<h4>Methods</h4>A total of 48 patients with T2DM were randomized to receive one of four doses of empagliflozin (2.5, 10, 25, or 100 mg qd) or placebo over 8 days. In every dose group, nine patients received active drug and three received placebo.  ...[more]

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