Drug Design, Development and Therapy (Apr 2021)
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
Yu Kyong Kim,1,* Jun Gi Hwang,1,* Min Kyu Park1,2 1Department of Clinical Pharmacology and Therapeutics, Chungbuk National University College of Medicine and Hospital, Cheongju, Republic of Korea; 2Department of Pharmacology and Clinical Pharmacology, Dong-A University College of Medicine, Dong-A University Hospital, Busan, Republic of Korea*These authors contributed equally to this workCorrespondence: Min Kyu ParkDepartment of Clinical Pharmacology and Therapeutics, Chungbuk National University College of Medicine and Hospital, 776, 1 Sunhwan-ro, Seowon-gu, Cheongju-si, Chungcheongbuk-do, 28644, Republic of KoreaTel +82 43 269 8708Fax +82 43 269 8724Email [email protected]: 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 (Cmax,ss) and area under the concentration-time curve over the dosing interval (AUCtau) 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 Cmax,ss and AUCtau, respectively). Likewise, empagliflozin did not affect lobeglitazone Cmax,ss or AUCtau (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
