Journal Article

Lack of Clinically Relevant Drug–Drug Interaction Between Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, and Verapamil, Ramipril, or Digoxin in Healthy Volunteers

Schoene, Katja, Sennewald, Regina, Pinnetti, Sabine, Woerle, Hans J., Rose, Peter, Broedl, Uli C., Macha, Sreeraj

2013

Overview

Empagliflozin is a sodium glucose cotransporter 2 inhibitor in clinical development as a treatment for type 2 diabetes mellitus. The goal of this study was to investigate potential drug–drug interactions between empagliflozin and verapamil, ramipril, and digoxin in healthy volunteers. 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. 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. 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).

• Publisher: EM Inc USA,Elsevier,Elsevier Limited
• Subject: Adolescent / Adult / Area Under Curve / Benzhydryl Compounds - blood / Benzhydryl Compounds - pharmacokinetics / Benzhydryl Compounds - pharmacology / Biological and medical sciences / Cross-Over Studies / Diabetes / Diabetes. Impaired glucose tolerance / digoxin / Digoxin - blood / Digoxin - pharmacokinetics / Digoxin - pharmacology / Drug dosages / Drug Interactions / Drug therapy / drug–drug interaction / empagliflozin / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Female / Glucosides - blood / Glucosides - pharmacokinetics / Glucosides - pharmacology / Half-Life / Humans / Internal Medicine / Male / Medical Education / Medical sciences / Metabolites / Middle Aged / Pharmacology. Drug treatments / ramipril / Ramipril - blood / Ramipril - pharmacokinetics / Ramipril - pharmacology / Reference Values / SGLT2 inhibitor / Sodium / Sodium-Glucose Transporter 2 - antagonists & inhibitors / type 2 diabetes / verapamil / Verapamil - blood / Verapamil - pharmacokinetics / Verapamil - pharmacology / Young Adult