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Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in Japanese patients with type 2 diabetes mellitus.
Clin Ther. 2014 Nov 01; 36(11):1606-15.CT

Abstract

PURPOSE

The purpose of this study was to assess the effect of renal impairment on the pharmacokinetic, pharmacodynamic, and safety profiles of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in Japanese patients with type 2 diabetes mellitus (T2DM).

METHODS

In an open-label, parallel-group study, 32 Japanese patients with T2DM and different degrees of renal function (n = 8 per renal function category: normal renal function, estimated glomerular filtration rate [eGFR; Japanese equation] ≥90 mL/min/1.73 m(2); mild renal impairment, eGFR of 60-<90 mL/min/1.73 m(2); moderate renal impairment, eGFR of 30-<60 mL/min/1.73 m(2); and severe renal impairment, eGFR of 15-<30 mL/min/1.73 m(2)) received a single 25 mg dose of empagliflozin.

FINDINGS

Empagliflozin exposure increased with increasing renal impairment. Maximum empagliflozin plasma concentrations were similar among all renal function groups. Adjusted geometric mean ratios for extent of exposure (AUC0-∞) to empagliflozin versus normal renal function were 128.8% (95% CI, 106.0-156.6%), 143.8% (95% CI, 118.3-174.8%), and 152.3% (95% CI, 125.3-185.2%) for patients with mild, moderate, and severe renal impairment, respectively. Decreases in renal clearance of empagliflozin correlated with eGFR. Urinary glucose excretion decreased with increasing renal impairment and correlated with eGFR (adjusted mean [SE] change from baseline: 75.0 [4.84] g, 62.6 [5.75] g, 57.9 [4.86] g, and 23.7 [5.24] g for patients with normal renal function and mild, moderate, and severe renal impairment, respectively). Only 2 patients (6%) had adverse events; both were mild.

IMPLICATIONS

Pharmacokinetic data suggest that no dose adjustment of empagliflozin is necessary in Japanese patients with T2DM and renal impairment because increases in exposure were <2-fold. Urinary glucose excretion decreased with increasing renal impairment. ClinicalTrials.gov identifier: NCT01581658.

Authors+Show Affiliations

Nippon Boehringer Ingelheim Co Ltd, Hyogo, Japan. Electronic address: akiko.sarashina@boehringer-ingelheim.com.Department of Molecular Sciences on Diabetes, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.Nippon Boehringer Ingelheim Co Ltd, Hyogo, Japan.Nippon Boehringer Ingelheim Co Ltd, Tokyo, Japan.Nippon Boehringer Ingelheim Co Ltd, Tokyo, Japan.Nippon Boehringer Ingelheim Co Ltd, Tokyo, Japan.Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany.Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany.Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany.Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut.

Pub Type(s)

Clinical Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25199997

Citation

Sarashina, Akiko, et al. "Effect of Renal Impairment On the Pharmacokinetics, Pharmacodynamics, and Safety of Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, in Japanese Patients With Type 2 Diabetes Mellitus." Clinical Therapeutics, vol. 36, no. 11, 2014, pp. 1606-15.
Sarashina A, Ueki K, Sasaki T, et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in Japanese patients with type 2 diabetes mellitus. Clin Ther. 2014;36(11):1606-15.
Sarashina, A., Ueki, K., Sasaki, T., Tanaka, Y., Koiwai, K., Sakamoto, W., Woerle, H. J., Salsali, A., Broedl, U. C., & Macha, S. (2014). Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in Japanese patients with type 2 diabetes mellitus. Clinical Therapeutics, 36(11), 1606-15. https://doi.org/10.1016/j.clinthera.2014.08.001
Sarashina A, et al. Effect of Renal Impairment On the Pharmacokinetics, Pharmacodynamics, and Safety of Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, in Japanese Patients With Type 2 Diabetes Mellitus. Clin Ther. 2014 Nov 1;36(11):1606-15. PubMed PMID: 25199997.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in Japanese patients with type 2 diabetes mellitus. AU - Sarashina,Akiko, AU - Ueki,Kohjiro, AU - Sasaki,Tomohiro, AU - Tanaka,Yuko, AU - Koiwai,Kazuki, AU - Sakamoto,Wataru, AU - Woerle,Hans J, AU - Salsali,Afshin, AU - Broedl,Uli C, AU - Macha,Sreeraj, Y1 - 2014/09/05/ PY - 2014/04/04/received PY - 2014/07/11/revised PY - 2014/08/01/accepted PY - 2014/9/10/entrez PY - 2014/9/10/pubmed PY - 2016/2/20/medline KW - Japanese patients KW - SGLT2 inhibitor KW - empagliflozin KW - pharmacodynamics KW - pharmacokinetics KW - renal impairment SP - 1606 EP - 15 JF - Clinical therapeutics JO - Clin Ther VL - 36 IS - 11 N2 - PURPOSE: The purpose of this study was to assess the effect of renal impairment on the pharmacokinetic, pharmacodynamic, and safety profiles of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: In an open-label, parallel-group study, 32 Japanese patients with T2DM and different degrees of renal function (n = 8 per renal function category: normal renal function, estimated glomerular filtration rate [eGFR; Japanese equation] ≥90 mL/min/1.73 m(2); mild renal impairment, eGFR of 60-<90 mL/min/1.73 m(2); moderate renal impairment, eGFR of 30-<60 mL/min/1.73 m(2); and severe renal impairment, eGFR of 15-<30 mL/min/1.73 m(2)) received a single 25 mg dose of empagliflozin. FINDINGS: Empagliflozin exposure increased with increasing renal impairment. Maximum empagliflozin plasma concentrations were similar among all renal function groups. Adjusted geometric mean ratios for extent of exposure (AUC0-∞) to empagliflozin versus normal renal function were 128.8% (95% CI, 106.0-156.6%), 143.8% (95% CI, 118.3-174.8%), and 152.3% (95% CI, 125.3-185.2%) for patients with mild, moderate, and severe renal impairment, respectively. Decreases in renal clearance of empagliflozin correlated with eGFR. Urinary glucose excretion decreased with increasing renal impairment and correlated with eGFR (adjusted mean [SE] change from baseline: 75.0 [4.84] g, 62.6 [5.75] g, 57.9 [4.86] g, and 23.7 [5.24] g for patients with normal renal function and mild, moderate, and severe renal impairment, respectively). Only 2 patients (6%) had adverse events; both were mild. IMPLICATIONS: Pharmacokinetic data suggest that no dose adjustment of empagliflozin is necessary in Japanese patients with T2DM and renal impairment because increases in exposure were <2-fold. Urinary glucose excretion decreased with increasing renal impairment. ClinicalTrials.gov identifier: NCT01581658. SN - 1879-114X UR - https://www.unboundmedicine.com/medline/citation/25199997/Effect_of_renal_impairment_on_the_pharmacokinetics_pharmacodynamics_and_safety_of_empagliflozin_a_sodium_glucose_cotransporter_2_inhibitor_in_Japanese_patients_with_type_2_diabetes_mellitus_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0149-2918(14)00495-0 DB - PRIME DP - Unbound Medicine ER -