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Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers.

Abstract：

BACKGROUND:Empagliflozin is a sodium glucose cotransporter 2 inhibitor in clinical development as a treatment for type 2 diabetes mellitus. OBJECTIVE:The goal of this study was to investigate potential drug-drug interactions between empagliflozin and verapamil, ramipril, and digoxin in healthy volunteers. METHODS:The potential drug-drug interactions were evaluated in 3 separate trials. In the first study, 16 subjects were randomized to receive single-dose empagliflozin 25 mg alone or single-dose empagliflozin 25 mg with single-dose verapamil 120 mg. In the second study, 23 subjects were randomized to receive empagliflozin 25 mg once daily (QD) for 5 days, ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days or empagliflozin 25 mg with ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days. In the third study, 20 subjects were randomized to receive single-dose digoxin 0.5 mg alone or empagliflozin 25 mg QD for 8 days with single-dose digoxin 0.5 mg on day 5. RESULTS:Exposure of empagliflozin was not affected by coadministration with verapamil (AUC0-∞: geometric mean ratio [GMR], 102.95%; 90% CI, 98.87-107.20; Cmax: GMR, 92.39%; 90% CI, 85.38-99.97) or ramipril (AUC over a uniform dosing interval τ at steady state [AUCτ,ss]: GMR, 96.55%; 90% CI, 93.05-100.18; Cmax at steady state [Cmax,ss]: GMR, 104.47%; 90% CI 97.65-111.77). Empagliflozin had no clinically relevant effect on exposure of ramipril (AUCτ,ss: GMR, 108.14%; 90% CI 100.51-116.35; Cmax,ss: GMR, 103.61%; 90% CI, 89.73-119.64) or its active metabolite ramiprilat (AUCτ,ss: GMR, 98.67%; 90% CI, 96.00-101.42; Cmax,ss: GMR, 98.29%; 90% CI, 92.67-104.25). Coadministration of empagliflozin had no clinically meaningful effect on digoxin AUC0-∞ (GMR, 106.11%; 90% CI, 96.71-116.41); however, a slight increase in Cmax was observed that was not considered clinically relevant (GMR, 113.94%; 90% CI, 99.33-130.70). All treatments were well tolerated. There were no serious adverse events or adverse events leading to discontinuation in any of the studies. CONCLUSIONS:No dose adjustment of empagliflozin is required when coadministered with ramipril or verapamil, and no dose adjustment of digoxin or ramipril is required when coadministered with empagliflozin. ClinicalTrials.gov identifiers: NCT01306175 (digoxin), NCT01276301 (verapamil), and NCT01284621 (ramipril).

journal_name

Clin Ther

journal_title

Clinical therapeutics

authors

Macha S,Sennewald R,Rose P,Schoene K,Pinnetti S,Woerle HJ,Broedl UC

doi

10.1016/j.clinthera.2013.02.015

subject

Has Abstract

pub_date

2013-03-01 00:00:00

pages

226-35

issue

eissn

0149-2918

issn

1879-114X

pii

S0149-2918(13)00071-4

journal_volume

pub_type

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Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers.