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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.
Clin Ther. 2013 Mar; 35(3):226-35.CT

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).

Authors+Show Affiliations

Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT 06877, USA. sreeraj.macha@boehringer-ingelheim.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23497760

Citation

Macha, Sreeraj, et al. "Lack of Clinically Relevant Drug-drug Interaction Between Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, and Verapamil, Ramipril, or Digoxin in Healthy Volunteers." Clinical Therapeutics, vol. 35, no. 3, 2013, pp. 226-35.
Macha S, Sennewald R, Rose P, et al. Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers. Clin Ther. 2013;35(3):226-35.
Macha, S., Sennewald, R., Rose, P., Schoene, K., Pinnetti, S., Woerle, H. J., & Broedl, U. C. (2013). Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers. Clinical Therapeutics, 35(3), 226-35. https://doi.org/10.1016/j.clinthera.2013.02.015
Macha S, et al. Lack of Clinically Relevant Drug-drug Interaction Between Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, and Verapamil, Ramipril, or Digoxin in Healthy Volunteers. Clin Ther. 2013;35(3):226-35. PubMed PMID: 23497760.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers. AU - Macha,Sreeraj, AU - Sennewald,Regina, AU - Rose,Peter, AU - Schoene,Katja, AU - Pinnetti,Sabine, AU - Woerle,Hans J, AU - Broedl,Uli C, PY - 2012/12/04/received PY - 2013/02/15/revised PY - 2013/02/15/accepted PY - 2013/3/19/entrez PY - 2013/3/19/pubmed PY - 2013/8/30/medline SP - 226 EP - 35 JF - Clinical therapeutics JO - Clin Ther VL - 35 IS - 3 N2 - 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). SN - 1879-114X UR - https://www.unboundmedicine.com/medline/citation/23497760/Lack_of_clinically_relevant_drug_drug_interaction_between_empagliflozin_a_sodium_glucose_cotransporter_2_inhibitor_and_verapamil_ramipril_or_digoxin_in_healthy_volunteers_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0149-2918(13)00071-4 DB - PRIME DP - Unbound Medicine ER -