Evaluation of pharmacokinetic interactions between lobeglitazone, empagliflozin, and metformin in healthy subjects

Abstract

Concomitant administration of lobeglitazone, empagliflozin, and metformin is expected to enhance blood glucose-lowering effects and improve medication compliance in patients with diabetes mellitus. In this study, we investigated the pharmacokinetic (PK) interactions and safety of lobeglitazone and co-administered empagliflozin and metformin, which are approved agents used in clinical settings. Two randomized, open-label, multiple-dose, 2-treatment, 2-period, 2-sequence crossover clinical trials (parts 1 and 2) were conducted independently. In part 1, lobeglitazone monotherapy or lobeglitazone, empagliflozin, and metformin triple therapy was administered for 5 days. In part 2, empagliflozin and metformin dual therapy or the abovementioned triple therapy were administered for 5 days. Serial blood samples were collected up to 24 hours after the last dose in each period for PK evaluation. The primary PK parameters (AUC_tau,ss, C_max,ss) of treatment regimens in each study part were calculated and compared. For lobeglitazone, the geometric mean ratios (GMRs) with 90% confidence intervals (CI) for triple therapy over monotherapy were 1.08 (1.03-1.14) for C_max,ss and 0.98 (0.90-1.07) for AUC_tau,ss. For empagliflozin, the GMRs and 90% CIs for triple therapy over dual therapy were 0.87 (0.78-0.97) for C_max,ss and 0.97 (0.93-1.00) for AUC_tau,ss. For metformin, the GMRs and 90% CIs for triple therapy over dual therapy were 1.06 (0.95-1.17) for C_max,ss and 1.04 (0.97-1.12) for AUC_tau,ss. All reported adverse events were mild. The triple therapy consisting of lobeglitazone, empagliflozin, and metformin did not show any clinically relevant drug interactions in relation to the PKs and safety of each drug substance.

Trial registration: ClinicalTrials.gov Identifier: NCT04334213.

Keywords: Diabetes Mellitus; Drug Interactions; Pharmacokinetics; Thiazolidinediones.

Figure 1. Mean (standard deviation) plasma concentration-time profiles at steady state of lobeglitazone when administered as monotherapy and as part of triple therapy. (A) Linear scale; (B) Semi-log scale.

LOB, administration of lobeglitazone 0.5 mg, once daily for 5 days; LOB + EMP + MET, administration of lobeglitazone 10 mg, empagliflozin 25 mg and metformin 1,000 mg 2 tablets, once daily for 5 days.

Figure 2. Mean (standard deviation) plasma concentration-time profiles at steady state of empagliflozin when administered as dual therapy and as part of triple therapy. (A) Linear scale; (B) Semi-log scale.

EMP + MET, administration of empagliflozin 25 mg and metformin 1,000 mg 2 tablets, once daily for 5 days; LOB + EMP + MET, administration of lobeglitazone 10 mg, empagliflozin 25 mg, and metformin 1,000 mg 2 tablets once daily for 5 days.

Figure 3. Mean (standard deviation) plasma concentration-time profiles at steady state of metformin when administered as dual therapy and as part of triple therapy. (A) Linear scale; (B) Semi-log scale.

EMP + MET, administration of empagliflozin 25 mg and metformin 1,000 mg 2 tablets, once daily for 5 days; LOB + EMP + MET, administration of lobeglitazone 10 mg, empagliflozin 25 mg, and metformin 1,000 mg 2 tablets, once daily for 5 days.