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Assessing pharmacokinetic interactions between the sodium glucose cotransporter 2 inhibitor empagliflozin and hydrochlorothiazide or torasemide in patients with type 2 diabetes mellitus: a randomized, open-label, crossover study.
Clin Ther. 2015 Apr 01; 37(4):793-803.CT

Abstract

PURPOSE

Empagliflozin is a potent, selective sodium glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus. Thiazide or loop diuretics are commonly prescribed in patients with type 2 diabetes mellitus. This study investigated potential pharmacokinetic drug-drug interactions between empagliflozin and hydrochlorothiazide (HCTZ) or torasemide (TOR).

METHODS

This was an open-label, crossover study. Patients with type 2 diabetes mellitus were randomized to receive empagliflozin 25 mg once daily for 5 days and either HCTZ 25 mg once daily for 4 days followed by HCTZ 25 mg once daily plus empagliflozin 25 mg once daily for 5 days or TOR 5 mg once daily for 4 days followed by TOR 5 mg once daily plus empagliflozin once daily for 5 days in 1 of 4 sequences, with at least a 7-day washout period between treatments. Pharmacokinetic parameters of empagliflozin, HCTZ, and TOR were assessed and standard bioequivalence criteria (80%-125%) were applied. Tolerability assessments included the frequency of adverse events and an investigator assessment of global tolerability.

FINDINGS

Mean (SD) age of the 22 patients treated was 54.0 (8.1) years and body mass index was 27.1 (3.7) kg/m(2). Coadministration of empagliflozin with HCTZ or TOR had no effect on exposure to empagliflozin, HCTZ, or TOR. Geometric mean ratios (90% CIs) for empagliflozin AUC over a uniform dosing interval and Cmax at steady state were 107.1% (90% CI, 97.1-118.1) and 102.8% (90% CI, 88.6-119.3), respectively, when coadministered with HCTZ versus administration alone, and 107.8% (90% CI, 100.1-116.1) and 107.5% (90% CI, 97.9-118.0), respectively, when coadministered with TOR versus administration alone. For HCTZ, the geometric mean ratios for AUC over a uniform dosing interval and Cmax at steady state were 96.3% (90% CI, 89.1-104.0) and 101.8% (90% CI, 88.6-116.9), respectively, and for TOR were 101.4% (90% CI, 99.1-103.9) and 104.4% (90% CI, 93.8-116.3), respectively, for combined treatment versus administration alone. The pharmacokinetic profiles of empagliflozin, HCTZ, and TOR were similar after administration alone and in combination. Global tolerability was good for all patients after each treatment, and no severe or serious adverse events were reported.

IMPLICATIONS

No pharmacokinetic drug-drug interaction was observed between empagliflozin and HCTZ or TOR. ClinicalTrials.gov identifier: NCT01276288.

Authors+Show Affiliations

Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany. Electronic address: tim.heise@profil.com.Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.

Pub Type(s)

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

Language

eng

PubMed ID

25636696

Citation

Heise, Tim, et al. "Assessing Pharmacokinetic Interactions Between the Sodium Glucose Cotransporter 2 Inhibitor Empagliflozin and Hydrochlorothiazide or Torasemide in Patients With Type 2 Diabetes Mellitus: a Randomized, Open-label, Crossover Study." Clinical Therapeutics, vol. 37, no. 4, 2015, pp. 793-803.
Heise T, Mattheus M, Woerle HJ, et al. Assessing pharmacokinetic interactions between the sodium glucose cotransporter 2 inhibitor empagliflozin and hydrochlorothiazide or torasemide in patients with type 2 diabetes mellitus: a randomized, open-label, crossover study. Clin Ther. 2015;37(4):793-803.
Heise, T., Mattheus, M., Woerle, H. J., Broedl, U. C., & Macha, S. (2015). Assessing pharmacokinetic interactions between the sodium glucose cotransporter 2 inhibitor empagliflozin and hydrochlorothiazide or torasemide in patients with type 2 diabetes mellitus: a randomized, open-label, crossover study. Clinical Therapeutics, 37(4), 793-803. https://doi.org/10.1016/j.clinthera.2014.12.018
Heise T, et al. Assessing Pharmacokinetic Interactions Between the Sodium Glucose Cotransporter 2 Inhibitor Empagliflozin and Hydrochlorothiazide or Torasemide in Patients With Type 2 Diabetes Mellitus: a Randomized, Open-label, Crossover Study. Clin Ther. 2015 Apr 1;37(4):793-803. PubMed PMID: 25636696.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Assessing pharmacokinetic interactions between the sodium glucose cotransporter 2 inhibitor empagliflozin and hydrochlorothiazide or torasemide in patients with type 2 diabetes mellitus: a randomized, open-label, crossover study. AU - Heise,Tim, AU - Mattheus,Michaela, AU - Woerle,Hans J, AU - Broedl,Uli C, AU - Macha,Sreeraj, Y1 - 2015/01/28/ PY - 2014/08/22/received PY - 2014/11/14/revised PY - 2014/12/21/accepted PY - 2015/2/1/entrez PY - 2015/2/1/pubmed PY - 2016/3/30/medline KW - drug−drug interaction KW - empagliflozin KW - hydrochlorothiazide KW - pharmacokinetic properties KW - torasemide SP - 793 EP - 803 JF - Clinical therapeutics JO - Clin Ther VL - 37 IS - 4 N2 - PURPOSE: Empagliflozin is a potent, selective sodium glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus. Thiazide or loop diuretics are commonly prescribed in patients with type 2 diabetes mellitus. This study investigated potential pharmacokinetic drug-drug interactions between empagliflozin and hydrochlorothiazide (HCTZ) or torasemide (TOR). METHODS: This was an open-label, crossover study. Patients with type 2 diabetes mellitus were randomized to receive empagliflozin 25 mg once daily for 5 days and either HCTZ 25 mg once daily for 4 days followed by HCTZ 25 mg once daily plus empagliflozin 25 mg once daily for 5 days or TOR 5 mg once daily for 4 days followed by TOR 5 mg once daily plus empagliflozin once daily for 5 days in 1 of 4 sequences, with at least a 7-day washout period between treatments. Pharmacokinetic parameters of empagliflozin, HCTZ, and TOR were assessed and standard bioequivalence criteria (80%-125%) were applied. Tolerability assessments included the frequency of adverse events and an investigator assessment of global tolerability. FINDINGS: Mean (SD) age of the 22 patients treated was 54.0 (8.1) years and body mass index was 27.1 (3.7) kg/m(2). Coadministration of empagliflozin with HCTZ or TOR had no effect on exposure to empagliflozin, HCTZ, or TOR. Geometric mean ratios (90% CIs) for empagliflozin AUC over a uniform dosing interval and Cmax at steady state were 107.1% (90% CI, 97.1-118.1) and 102.8% (90% CI, 88.6-119.3), respectively, when coadministered with HCTZ versus administration alone, and 107.8% (90% CI, 100.1-116.1) and 107.5% (90% CI, 97.9-118.0), respectively, when coadministered with TOR versus administration alone. For HCTZ, the geometric mean ratios for AUC over a uniform dosing interval and Cmax at steady state were 96.3% (90% CI, 89.1-104.0) and 101.8% (90% CI, 88.6-116.9), respectively, and for TOR were 101.4% (90% CI, 99.1-103.9) and 104.4% (90% CI, 93.8-116.3), respectively, for combined treatment versus administration alone. The pharmacokinetic profiles of empagliflozin, HCTZ, and TOR were similar after administration alone and in combination. Global tolerability was good for all patients after each treatment, and no severe or serious adverse events were reported. IMPLICATIONS: No pharmacokinetic drug-drug interaction was observed between empagliflozin and HCTZ or TOR. ClinicalTrials.gov identifier: NCT01276288. SN - 1879-114X UR - https://www.unboundmedicine.com/medline/citation/25636696/Assessing_pharmacokinetic_interactions_between_the_sodium_glucose_cotransporter_2_inhibitor_empagliflozin_and_hydrochlorothiazide_or_torasemide_in_patients_with_type_2_diabetes_mellitus:_a_randomized_open_label_crossover_study_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0149-2918(14)00879-0 DB - PRIME DP - Unbound Medicine ER -