No Relevant Pharmacokinetic Drug–Drug Interaction Between the Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin and Lobeglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, in Healthy Subjects

Abstract

Purpose

Combination therapy with insulin-independent sodium-glucose cotransporter 2 inhibitors and thiazolidinedione drugs, such as lobeglitazone, has been reported to elicit potential additive efficacy in glycemic control in type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetic (PK) drug–drug interactions between empagliflozin and lobeglitazone in healthy subjects.

Subjects and Methods

A randomized, open-label, multiple-dose study was conducted in 30 healthy subjects using a three-treatment, six-sequence, three-way crossover design. Subjects received one of the following treatments once daily for 5 days in each period: 25 mg empagliflozin, 0.5 mg lobeglitazone sulfate, or a combination. Serial blood sampling before every dose and up to 24 h after the last dose was performed during each treatment period. The PK parameters were estimated using noncompartmental methods with the plasma empagliflozin and lobeglitazone concentrations. The absence of a PK interaction was construed as the 90% confidence interval (90% CI) of maximum concentration at steady state (C_max,ss) and area under the concentration-time curve over the dosing interval (AUC_tau) for combination therapy-to-monotherapy ratios within the limits of 0.80–1.25.

Results

The steady-state plasma empagliflozin and lobeglitazone concentration-time profiles of combination therapy and monotherapy were comparable in the 25 subjects who completed the study. Coadministration of empagliflozin with lobeglitazone did not affect empagliflozin PK (with 90% CIs of 0.956–1.150 and 0.945–1.133 for C_max,ss and AUC_tau, respectively). Likewise, empagliflozin did not affect lobeglitazone C_max,ss or AUC_tau (with 90% CIs of 0.869–0.995 and 0.851–1.018, respectively). All treatment groups tolerated mild adverse events well.

Conclusion

The lack of PK interactions between lobeglitazone and empagliflozin in combination therapy, along with their good tolerability, indicates that the two drugs can be coadministered without dose adjustment.

Trial Registration Number

NCT02854748, Registered on August 7, 2016.

Keywords:

• clinical trial
• antidiabetic drug
• pharmacokinetic interaction
• thiazolidinedione
• type 2 diabetes

Abbreviations

AUC, area under the plasma concentration-time curve; AUC_tau, area under the plasma concentration-time curve during a dosage interval; C_max,ss, maximum steady-state plasma concentration during a dosage interval; C_trough, trough plasma concentration measured at the end of a dosing interval at steady state taken directly before next administration; %DMT, percentage deviation of the mean from the theoretical concentration; EDTA, ethylenediaminetetraacetic acid; HbA1C, hemoglobin A1C; ISTD, internal standard; MRM, multiple reaction monitoring; PK, pharmacokinetic; RSD, relative standard deviations; SGLT-2, sodium-glucose cotransporter 2; t_1/2,ss, terminal half-life; T2DM, type 2 diabetes mellitus; T_max,ss, time to reach maximum plasma concentration following drug administration at steady state; TZD, thiazolidinedione; UPLC, ultra-performance liquid chromatography.

Data Sharing Statement

The dataset supporting the conclusions of this article is included in the article.

Ethics Approval and Informed Consent

Prior to the study conduct, the clinical study protocol was approved by the Dong-A University Hospital Institutional Review Board. The study was conducted in subjects who have provided a written informed consent, under the principles stipulated in the Declaration of Helsinki and the International Council on Harmonization Good Clinical Practice Guideline.^22,23

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This study was sponsored by Chong Kun Dang Pharm.